cell cycle regulation in plant development
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Cell Cycle Regulationin Plant Development1
Dirk Inze and Lieven De Veylder
Department of Plant Systems Biology, Flanders Interuniversity Institute forBiotechnology (VIB), Ghent University, Technologiepark 927, B-9052 Gent,Belgium; email: dirk.inze@psb.ugent.be, lieven.deveylder@psb.ugent.be
Annu. Rev. Genet. 2006. 40:77105
First published online as a Review inAdvance on September 1, 2006
TheAnnual Review of Geneticsis online athttp://genet.annualreviews.org
This articles doi:10.1146/annurev.genet.40.110405.090431
Copyright c2006 by Annual Reviews.All rights reserved
0066-4197/06/1215-0077$20.00
1NOMENCLATURE
By convention all names for plant genesare in uppercase italics, proteins inuppercase roman, and mutant genes or
alleles in lowercase italics. Much of thework described has been generated withArabidopsis thalianaas experimentalsystem. When no species reference isgiven for any gene, protein, or mutant, itshould be understood that it refers toArabidopsisresearch. In all other cases, thespecies name is mentioned.
Key Words
Arabidopsis, cell cycle, cyclin, cyclin-dependent kinase,
endoreduplication, plant development
Abstract
Cell cycle regulation is of pivotal importance for plant growth an
development. Although plant cell division shares basic mechanism
with all eukaryotes, plants have evolved novel molecules orchestrat
ing the cell cycle. Some regulatory proteins, such as cyclins and
inhibitors of cyclin-dependent kinases, are particularly numerous in
plants, possibly reflecting the remarkable ability of plants to modu
late their postembryonicdevelopment. Many plant cells also cancon
tinue DNA replication in the absence of mitosis, a process known a
endoreduplication, causing polyploidy. Here, we review the molec
ular mechanisms that regulate cell division and endoreduplicationand we discuss our understanding, albeit very limited, on how th
cell cycle is integrated with plant development.
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Meristem: tissueundergoing mitosis,giving rise to newcells and tissues
Pluripotent:property ofdifferentiated cell toreinitiate celldivision to generatenew plant organs
SAM: shoot apicalmeristem
Contents
INTRODUCTION . . . . . . . . . . . . . . . . . 78
UNIQUE FEATURES OF PLANT
CELL DIVISION . . . . . . . . . . . . . . . 78
THE BASIC CELL CYCLE
MACHINERY. . . . . . . . . . . . . . . . . . . 79
Cyclin-Dependent Kinases . . . . . . . . 79Cyclins . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Proteolysis . . . . . . . . . . . . . . . . . . . . . . . 84
CDK Phosphorylation. . . . . . . . . . . . 85
CDK Inhibitors . . . . . . . . . . . . . . . . . . 86
The RBR/E2F/DP Pathway . . . . . . 87
CELLULAR VERSUS
ORGANISMAL THEORY. . . . . . . 89
ENDOREDUPLICATION . . . . . . . . . 90
CONCLUDING REMARKS . . . . . . . 93
INTRODUCTION
The cell cycle is one of the most compre-hensively studied biological processes, partic-
ularly given its importance for growth and
development and deregulation in many hu-
man disorders. No other field has benefited
as much as the cell cycle from an extensive in-
terplay between research performed on a di-
versity of model organisms. Studies on yeast,
worms, flies, frogs, mammals, and plants have
contributed to a universal picture on how thebasic cell cycle machinery is regulated, and
research on these many divergent organisms
is also elucidating how evolution modified
the basic cell cycle machinery to cope with
the specific developmental and environmen-
tal challenges of each organism. However, this
picture is mainly based on experiments per-
formed on single cells. Indeed, the role of thecell cycle machinery during development has
received relatively little attention. To under-
stand how, in different organisms, the basic
cell cycle machinery integrates with devel-
opment remains an important scientific chal-
lenge. With this review, we hope to convince
the reader that plants offer exceptional op-
portunities to contribute significantly to such
a challenge.
UNIQUE FEATURES OF PLANTCELL DIVISION
In contrast to animals, plant development i
largely post-embryonic. New organs, such aroots, stems, leaves, and flowers, originat
from life-long iterative cell divisions followed
by cell growth and differentiation. Such cel
divisions occur at specialized zones known ameristems. Leaves and flowers are formed a
the shoot and floral meristems, respectively
whereas the root meristems continuously add
new cells to the growing root. The cells athe meristem are pluripotent so that thei
progeny can become committed to a spectrum
of developmental fates. Initially, the shoot api
cal meristem (SAM) produces leaves, but un
der the right developmental or environmenta
conditions, the SAM will be converted into a
floral meristem that produces flowers.Another interesting aspect of many dif
ferentiated plant cells is their ability to dedifferentiate and acquire pluripotentiality, a
feature that allows an even larger develop
mental plasticity (70, 172, 173). For example
quiescent root pericycle cells can be stimu
lated to undergo cell divisions and to form
lateral roots de novo (22). On the other hand
root cortical cells ofFabaceaecan initiate cel
division to produce large nitrogen-fixing nod
ules upon infection with symbiotic bacteriathe Rhizobia (65). In another well-known ex
ample, protoplasts of leaf mesophyll cells can
construct a new cell wall, divide, and regen
erate roots or shoots upon treatment with ap
propriate plant growth factors (67).
Development of plants is also unique be
cause rigid cell walls surrounding plant cell
prevent any cell migration. Consequently, local cell-division parameters, such as the num
ber of cells produced at the meristems and
the cell division plane, are important in determining the organization of plant tissues
as illustrated by the scarecrow mutant, in
which the deficiency of a specific asymmetri
division event in one of the descendants o
the root stem cells results in lack of a complete root cell layer (44). Furthermore, the
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rigid cell wall prevents cytokinesis by means
of constriction (as is the case for animal cells).
Therefore, plants have developed an elab-
orate mechanism to generate two daughtercells that involves two unique cytoskeletal ar-
rays, termed the preprophase band (PPB) and
the phragmoplast (4, 163, 164). Another in-
teresting feature of plant cells is that, unlike
mammalian cells, they do not develop tumors,
except as specialized responses to certain
pathogens (48).
THE BASIC CELL CYCLEMACHINERY
Any discussion on the role of cell division
in plant development and growth requires a
thorough understanding of the basic machin-
ery that controls the cell cycle. As in other eu-
karyotic organisms, cyclin-dependent kinases
(CDKs) govern the plant cell cycle. Differ-
ent CDK-cyclin complexes phosphorylate aplethora of substrates at the key G1-to-S and
G2-to-M transition points, triggering the on-
set of DNA replication and mitosis, respec-
tively. The catalytic CDK subunit is respon-
sible for recognizing the target motif (a serine
or threonine followed by a proline) present in
substrate proteins, whereas the exchangeable
regulatory cyclins play a role in discriminatingdistinct protein substrates.
Cyclin-Dependent Kinases
All eukaryotic organisms studied to date pos-
sess at least one CDK with the PSTAIRE hall-
mark in their cyclin-binding domain. In plants
too, a bona fide PSTAIRE CDK, designated
CDKA, plays a pivotal role at both the G1-to-S and G2-to-M transition points (Figures 1
and 2). The universal nature of PSTAIRE
CDKs is best illustrated by their ability to
complement functionally CDK-deficient mu-
tants of yeasts (58, 80). CDKA protein lev-
els remain constant throughout the cell cycle
(116, 137, 168). Overproduction of a domi-
nant negative CDKA ofArabidopsis thaliana in
tobacco(Nicotiana tabacum)plantsresultsinan
Preprophase band(PPB): cytoskeletalarray encircling thecell plate inside theplasma membrane athe site where the
future cell wall willjoin the parent wall
Phragmoplast:cytokinetic organellconsisting of parallealigned microtubuleand actin filamentsthat participate in thbuilding of a new cewall by targeting celwall material to thegrowing cell plate
CDKs:cyclin-dependentkinases
overall reduction of the cell division rate, thus
yielding smaller plants. However, the G1/G2
ratio remains unaltered, corresponding with
the observation that CDKA activity can bedetected at both checkpoints (78, 92, 138).
Thus, CDKA is essential at both the G1-to-
S and G2-to-M transitions of the cell cycle.
The requirement of CDKA at least for entry
into mitosis has been demonstrated by null
mutants, whose primary defect appears to be
a failure to progress through the second mi-
tosis during male gametophytic development
(86, 132).No orthologs of the mammalian G1/S-
specificCDK4andCDK6genes are present in
plants. As such, CDKA is seemingly the only
CDK active at the G1 and S phases in plant
cells, whereas the entry into mitosis is proba-
bly controlled by multiple CDKs (Figure 2).
Plants possess a unique class of CDKs, the so-
called B-type CDKs that have not been de-
scribed for any other organism (16, 80, 91).The PSTAIRE hallmark present in CDKAs is
replaced by either PPTALRE or PPTTLRE,
reflecting the existence of two subgroups,
CDKB1 and CDKB2 (186). Arabidopsishar-
bors two CDKB1 (CDKB1;1 and CDKB1;2)
and CDKB2 (CDKB2;1 and CDKB2;2) fam-
ily members. The two CDKB subgroups are
found in both monocotyledonous and di-cotyledonous species, suggesting a conserved
unique role for each of the CDKB subgroups
in cell cycle regulation, but have a slightly dif-
ferent timing in cell cycle phasedependent
transcription.CDKB1transcripts accumulate
during S, G2, and M phases, whereasCDKB2
expression is specific to the G2 and M phases
(18, 31, 60, 116, 123, 125, 138, 159, 168, 185).
The accumulation of CDKB proteins followstheir transcription pattern, and their associ-
ated kinase activity reaches a maximum during
mitosis. The requirement for CDKB1 activity
to progress through mitosis has been demon-
strated with a dominant negative approach,
illustrating that a reduction in CDKB1 activ-
ity results in an increased 4C/2C ratio be-
cause of a block at the G2-to-M transition(15, 138).
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KRP
CYCD2/4
CYCD3
Sucrose
CytokininBR
CDKA Auxin
CDKA
CYCD
CDKA
CYCD
T160
InactiveCDK/cyclincomplex
ActiveCDK/cyclincomplex
CDKD
ABACold
Auxin
DPTargeted fordestruction
DPE2Fc
E2Fc
DPE2Fa/b
E2Fa/b
SCF
DP
Expression of S phase genes
RBR
RBR
RBR
CYCH
InactiveE2F/DPcomplex
Active E2F/DPcomplex
S
G1
G1-S transition
DEL
CDKF
P PP
P
P
Figure 1
Schematic representation of the regulation of the G1-to-S transition in plants. In the presence of growthfactors [such as sucrose, auxin, cytokinin, and brassinosteroids (BR)] D-type cyclins (CYCD) associatewith the A-type CDK (CDKA), forming an inactive CDKA/CYCD complex. This complex is probablyactivated through phosphorylation by the CDK-activating kinase pathway, which involves CDKF andCDKD associated with an H-type cyclin (CYCH). Full activation of the CDKA/CYCD complexrequires as well the phosphorylation of the CYCD subunit by an as-yet unknown kinase (not shown). Inresponse to antimitogenic stimuli, such as abscisic acid (ABA) and cold, KRPs can inhibit the activatedCDK/CYCD complexes. CDKA/CYCD complexes trigger the G1-to-S transition via two parallelpathways. On the one hand, CDKA/CYCD phosphorylation will initiate the destruction of theE2Fc/DP/RBR transcriptional repressor complex by the SCF E3-ubiquitin-protein ligase; on the otherhand, RBR phosphorylation will release the transcriptional activity of the E2Fa-b/DP/RBR complexes.As a result, the expression of S-phase genes is activated. The atypical E2F-like DEL transcription factor
might fine-tune the expression of a subset of E2F target genes.
Remarkably, both Chlamydomonas rein-
hardtiiandOstreococcus tauricontain only one
CDKBgene that resembles theCDKB1genes
of higher plants (11, 149). The O. tauriCDKB
contains a novel cyclin-binding motif that is
midway between the PSTAIRE CDKA andthe P[S/P]T[A/T]LRE CDKB motifs. Just a
observed for CDKBs of higher plants, the
CDKB protein levels and activity in O. taur
appear to be regulated by the cell cycle (31)
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Surprisingly, O. tauriCDKB complements a
CDK mutant of budding yeast (Saccharomyces
cerevisiae), whereas the higher plant orthologs
are unable to do so (31, 80, 137).Plants that overexpress a dominant nega-
tive allele ofCDKB1;1have abnormal stom-
ata and a decreased number of stomatal com-
plexes. This feature indicates a specific role
for CDKB1 in the series of sequential divi-
sions required to form a stomatal complex,
as substantiated by the strong expression of
CDKB1;1observed in all progenitor cells of
stomatal complexes (15). In addition, CDKB1has also been demonstrated to control the on-
set of cell cycle exit (17) (see below).
CDK activity is regulated by phosphory-
lation. Phosphorylation of Thr160 (or the
equivalent residue) of CDKs induces a con-
formational change allowing proper recog-
nition of substrates and is performed by
CDK-activating kinases (CAKs). Arabidop-
sis contains four CAK-encoding genes, di-vided into two functional classes (CDKD and
CDKF; Figures 1 and 2) (182, 183, 186,
207). CDKD is functionally related to ver-
tebrate CAKs, whereas CDKF is a plant-
specific CAK displaying unique enzyme char-
acteristics. The functional diversity between
the two CAK classes is exemplified by their
substrate specificity and cyclin dependence.Only CDKDs phosphorylate the C-terminal
domain (CTD) of the largest subunit of RNA
polymerase II. Moreover, in contrast to the
CDKDs, activation of CDKF requires no as-
sociation with H-type cyclin (CYCH) (206).
Recently, CDKF has been shown to phos-
phorylate and activate CDKDs inArabidopsis
(161) (Figures 1and2).
Through their regulation of CDK activity,CAKs have been shown to be potentially im-
portant regulators of the cell cycle in response
to endogenous hormone gradients. Whereas
normally undifferentiated callus cells can be
induced only from leaf tissue by applying both
auxin and cytokinin, calli derived from plants
overproducing a rice (Oryza sativa) CDKD
grew independently of cytokinin. This effectrelied on the activation of CDK activity and
Ostreococcus tauri:unicellular green algthat was discoveredin the MediterraneaThau lagoon
CAKs:
CDK-activatingkinases
CTD: C-terminaldomain
CYC: cyclin
RBR:retinoblastoma-relatedprotein
HEN3: HUAENHANCER3
could even be enhanced by the co-production
of CYCH (206). Likewise, inducible down-
regulation of CDKF activity resulted in a
gradual reduction in CDK activity and a pre-mature differentiation of root meristem cells
(184), whereas increased expression of the
riceCDKD;1(also known asR2) accelerated
S-phase progression and the overall growth
rate of suspension cells (56). These data in-
dicate that CAKs play an important role in
determining the growth rate and the differen-
tiation status of cells by controlling the overall
level of CDK activity.Plants also contain C-type and E-type
CDK-related genes, designated CDKC and
CDKE, with no clear role in cell cycle con-
trol. CDKCs contain PITAIRE or SPTAIRE
hallmarks, interact with CYCT, and play a
presumed role in transcription elongation
by phosphorylating the CTD of RNA poly-
merase II (6, 63, 94). A CDKC/CYCT com-
plex ofMedicago truncatula phosphorylates theretinoblastoma-related (RBR) protein as well,
suggesting that, like their mammalian coun-
terparts, plant CDKCs might control cellu-
lar differentiation through RBR inactivation
(63). In agreement with this postmitotic role
for CDKC, transcripts were found mainly in
differentiated tissues (6, 93).
CDKE contains a SPTAIRE motif and isidentical to HUA ENHANCER3 (HEN3)
(197). Phenotypic characterization of hen3mutants demonstrated that CDKE acts in cell
expansion in leaves and cell-fate specification
in floral organs. Like CDKCs, CDKE phos-
phorylatesCTD of RNApolymerase II, but in
contrast, is produced in dividing tissues (197).
Cyclins
Little is known to date on the interaction
of cyclins with CDKs. This lack of informa-
tion stems in part from the observation that
plants contain many more cyclins than pre-
viously described in other organisms (186).
For example, despite its small genome size,
A. thalianahas at least 32 cyclins with a puta-
tive role in cell cycle progression. The plant
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CYCD
CYCA
CDKA
CDKA/B
CYC
CYC
T160
CDK/cyclincomplexformation
InactiveCDK/cyclincomplex
CDKD
CYCH
G2
G2-M transition
CDKF
CYCB
CDKB
WEE1Stress
CDKA/B
CYC
CDKA/B
InactiveCDK/cyclincomplex
Y15T14
CYC
ActiveCDK/cyclincomplex
CDKA/B
CDC25
CCS52
T160
Y15T14
Entry into mitosis
Cyclindegradation
?
CYC
ActiveCDK/cyclincomplex
CDKA/B
T160
Exit of mitosis
APC
M-G1 transition
M
G1
P P
P P
P
P
P
DPE2Fa/b
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cyclin nomenclature is based on the functional
similarity with the mammalian counterparts.
Arabidopsisgene annotation identified 10 A-
type, 11 B-type, 10 D-type, and 1 H-type cy-clins (186, 193). In addition, at least 17 other
cyclin-related genes have been found in the
Arabidopsisgenome and are classified in types
C, P, L, and T (179, 193). Although some of
these cyclin members have been found to as-
sociate with CDKs, a function in the cell cycle
has not been demonstrated for any of them.
In a broad sense, D-type cyclins are
thought to regulate the G1-to-S transition,A-type cyclins, the S-to-M phase control,
and B-type cyclins both the G2-to-M transi-
tion and intra-M-phase control (19, 126, 140)
(Figures 1 and 2). A number of deviations
of this general functional assignment have
been reported. For Medicago sativa, CYCA2
has been shown to contribute to cell cycle
specific kinase activity, not only at the entry
to the S phase, but also during the G2-to-Mtransition (151). In contrast to animals, some
preliminary evidence points to an additional
function of D-type cyclins at the G2-to-M
transition. For example, CYCD4;1 has been
found to associate and activate the G2/M-
specific CDKB2;1 in vitro (100). In addition,
ectopic expression ofCYCD3;1 in trichomes
not only promotes S-phase entry but also in-duces mitosis (155). Likewise, induced over-
expression of the tobacco CYCD3;3 and the
snapdragon (Anthirrhinum majus) CYCD1;1in tobacco Bright Yellow-2 (BY-2) cell sus-
pensions stimulated both S phase and mitotic
BY-2: fast-growingtobacco cell culture,comparable to Helacells for humanresearch
E2F: E2
promoter-bindingfactor
entry (101, 129). These data should, how-
ever, be interpreted with caution because a
mechanism might exist by which the activa-
tion of DNA replication stimulates mitoticentry, as demonstrated by the observation that
transcription of theCDKB1;1gene is at least
in part controlled by the G1/S-specific E2F
transcription factors (17, 115). In such a sce-
nario, any positive effect on the G1-to-S tran-
sition would result in the activation of later
cell cycle phases as well. In addition, it re-
mains possible that by ectopic expression of
the cyclin subunit, CDK/CYCD complexesare formed that do not exist during normal
development. On the other hand, in favor of a
direct involvement of D-type cyclins in con-
trolling the G2-to-M transition, some D-type
cyclins show a transcriptional peak at the G2-
to-M transition(124, 125, 166). Furthermore,
CYCD3;3-associated kinases were found to
be active at both the G1/S and G2/M bound-
aries (129).D-type cyclins have a large sequence di-
vergence and were originally identified by
functional complementation of a yeast strain
deficient for G1 cyclins (34, 165). In Ara-
bidopsis, the 10 CYCDs are classified into
seven groups, designatedCYCD1 to CYCD7,
with the CYCD3 and CYCD4 groups consist-
ing of three and two members, respectively(186). Although the complexity of plant cy-
clins can be attributed partly to extensive du-
plications of theArabidopsisgenome (162), the
large number of cyclins might reflect the high
developmental plasticity of sessile plants to
Figure 2
Schematic representation of the regulation of the G2-to-M transition in plants. During the G2 phase ofthe cell cycle, cyclins of the A, B, and probably D types (CYCA, CYCB, and CYCD) associate with bothCDKs of the A and B types (CDKA and CDKB). Some B-type CDKs are under transcriptional control
of the E2F pathway, probably providing a mechanism by which the G1-to-S and G2-to-M transitionscommunicate. The CDK-activating kinase pathway, involving CDKF and CDKD associated with anH-type cyclin (CYCH), controls the activity of the distinct CDK/CYC complexes. CDK activity can benegatively regulated by phosphorylation by the WEE1 kinase, which is triggered upon loss of DNAintegrity. The CDC25-related kinase, if existing, which removes the inhibitory phosphate groups, stillneeds to be identified. Once the CDK/CYC complexes are active, they trigger the G2-to-M transitionthrough the phosphorylation of a plethora of different substrates. Exit from mitosis requires theproteolytic destruction of the cyclin subunits. This destruction is initiated by the activation of theanaphase-promoting complex (APC) through its association with the CCS52 protein.
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Physcomitrellapatens: mossenabling directloss-of-functionstudies by genetargeting
respond to both intrinsic developmental sig-
nals and extrinsic environmental cues. Pos-
sibly, the complex cell cycle machinery is the
trade-off for the tremendous plasticity and ro-bustness of plant growth, which require the
presence of flexible regulatory networks. The
different cyclins might possess a wide range of
expression patterns and confer different sub-
strate specificities.
The expression of D-type cyclin genes is
modulated by plant growth factors, such as
cytokinins, auxins, brassinosteroids, sucrose,
and gibberellins (62, 68, 81, 121, 133, 146148, 154, 165). Some D-type cyclins proba-
bly act as key switches in triggering hormonal
effects. For example, expression ofCYCD3;1appears to be rate-limiting for cell division
in calli deprived of cytokinin. Correspond-
ingly, overexpression ofCYCD3;1is sufficient
to compensate for the lack of cytokinins in the
culture medium (147). Similarly, CYCD2;1
seems to stimulate the progression throughG1 in roots and shoots, leading to a faster
growth rate of transgenic tobacco plants over-
expressing CYCD2;1(29). There is probably
an extensive functionalredundancy among D-
type cyclins, because the genome-wide inser-
tional mutagenesis surveys have yet to report
severe phenotypes for D-cyclin knockouts
(21, 177). To date, some specific D-type cy-clin knockouts displayed only a slightly de-
layed cell cycle reactivation in the root meris-
tem during seed germination, supporting the
anticipated important role for D-type cyclins
in the regulation of cell cycle entry upon
meristem activation (119). Analogously, a cycD
knockout in the mossPhyscomitrella patenshas
a surprisingly limited phenotype. While wild-
type plants react to exogenous glucose sourceswith prolonged growth of juvenile stages and
retarded differentiation, cycD knockouts ex-
hibited developmental progression indepen-
dently of the sugar supply. However, growth
rate, cell size, or plant size were not affected.
These data suggest that the Physcomitrella
CYCD is not essential for cell cycle progres-
sion but seems important for coupling the de-velopment to nutrient availability (111).
Just as for D-type cyclins, only margina
phenotypes have been reported for CYCA
mutants. In tardy asynchronous meiosis (tam)the substitution of a conserved amino acid
residue probably results in an incorrect fold
ing of CYCA1;2, causing a slower cell cycl
progression during male meiosis (113, 198)
Knockouts for CYCA2;3 display a slight in
crease in their DNA ploidy level (85). In
both cases, the occurrence of only relatively
mild phenotypes can be explained by the fac
that these particular A-type cyclins are parof a family of closely related genes; as such
multiple knockouts will presumably have to
be combined before any severe phenotyp
is revealed. It is even likely that combin
ing multiple knockouts will result in embryo
lethality, as suggested by the observed de
fects on embryo formation upon antisens
expression of the tobacco CYCA3;2 cyclin
(208).In contrast to their knockdown, overex
pression of the A-type cyclin genes triggers an
acute phenotype:Arabidopsisplants that over
produce the tobacco CYCA3;2 cyclin show
ectopic cell division and delayed differentia
tion, correlated with an increase in expression
of S phasespecific genes and CYCA3;2
associated CDK activity. In addition, overproduction of CYCA3;2 impairs shoot and roo
regeneration in tissue culture (208). Thes
data indicate that for cell differentiation the
CDK activity must be down-regulated.
The potential of B-type cyclins to trig
ger the G2-to-M transition was originally
shown by microarray injection experiment
in oocytes ofXenopus laevis(77) and later by
illustrating that ectopic CYCB1;1 expressionpromotes root growth (47). CYCB1;1 wa
demonstrated in vitro to interact with and ac
tivate both A- and B-type CDKs (199).
Proteolysis
Proteolysis ensures that the cell cycle move
unidirectionally by triggering the rapid pro
teolysis of target proteins, thus providing an
irreversible mechanism that drives the cycl
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forward. In all cases, the route to destruction
runs via the ubiquitin-proteasome system,
which uses the highly conserved polypeptide
ubiquitin as a tag to mark target proteins fordegradation by the 26S proteasome. Ubiquiti-
nation requires the generation of polyubiqui-
tin chains on target proteins through the com-
bined action of ubiquitin-carrying enzymes
(or E2s) and ubiquitin-protein ligases (or E3s)
that bring targets and E2s together (135).
Two related E3 complexes are most intimately
dedicated to basic cell cycle control, namely
the anaphase-promoting complex (APC)and the Skp1/Cullin/F-box (SCF)-related
complex (192).
Plant cyclins are, as in other organisms,
subject to extensive regulation by proteoly-
sis. A- and B-type cyclins contain destruction
box (D-box) sequences that mediate protein
degradation (69, 145). B1 cyclins, a subclass
of B-type cyclins, are the substrate for the
ubiquitin-dependent protein ligase complexthat strongly resembles APC (32). The illus-
tration for the functional significance of this
cyclin destruction is that constitutive overex-
pression of a non-degradable B1 cyclin, lack-
ing the destruction box, causes severe growth
retardation and abnormal development with
a higher percentage of cells exhibiting dupli-
cated ploidy levels than the controls (199).Ectopic expression ofCYCA2;3 that lacks a
functional destruction box stabilizes protein
levels in plants and results in dwarfism (85).
On the other hand, proteolysis of B2 cyclins
at prometaphase appears to be proteasome in-
dependent (200).
Recently, CYCD3;1, but not CYCD2;1,
has been shown to be a highly unstable
protein whose proteolysis is mediated bya proteasome-dependent pathway (136). In
concert, the CYCD3;1 protein is stabilized in
mutant plants, defective in a ring-box (RBX1)
protein part of the plant SCF complexes
(108). Many D cyclins isolated to date contain
PEST sequences, regions rich in Pro, Glu,
Ser, and Thr, suggesting that they are labile
proteins degraded through a pathway similarto that of animal D-type cyclins (133, 165).
Proteasome:multisubunitcomplex involved inprotein breakdown
E2s:ubiquitin-carrying
enzymes
E3s:ubiquitin-proteinligases
APC:anaphase-promotingcomplex
SCF:Skp1/Cullin/F-boxprotein
CYCD1 instability also depends on the pro-
teasome, whereas CDKA amounts are unaf-
fected by the proteasome inhibitor MG132
(101). Other cell cycle regulators, such asCDC6 (24), CDT1a (23), E2Fc (42), and
the CDK inhibitor ICK2/KRP2 (188), are
destroyed via the ubiquitin/26S proteasome
pathway as well. It is not yet known which of
the 694 F-box proteins ofArabidopsis(189) are
involved in the specific recognition of the cell
cycle regulatory proteins.
Proteins that are degraded through the
proteasome frequently require prior phos-phorylation. TheArabidopsisCDT1a contains
multiple CDK phosphorylation sites, suggest-
ing that they might affect CDT1a regula-
tion (23). In concert, treatment ofArabidop-
sis seedlings with roscovitine, a well-known
CDK inhibitor, causes CDT1a to accu-
mulate (23). Also ICK2/KRP2 proteolysis
seems to be preceded by CDK-dependent
phosphorylation (188).The activation and substrate specificity of
the APC complex is in part determined by
two adaptor proteins, CDC20 and CDH1.
TheArabidopsisgenome encodes fiveCDC20
genes, as well as three CDH1-related pro-
teins, designated CCS52A1, CCS52A2, and
CCS52B (178). In Schizosaccharomyces pombe,
expression of the three Arabidopsis CCS52genes elicits distinct phenotypes, supporting
a nonredundant function of the CCS52 pro-
teins. Consistent with these different func-
tions,CCS52Bis expressed from G2/M to M,
whereas CCS52A1 and CCS52A2 arefromlate
M until early G1, suggesting consecutive ac-
tions of these APC activators in the plant cell
cycle. In addition, the CCS52 proteins inter-
act with different subsets of mitotic cyclins,either in free or CDK-bound forms (64).
CDK Phosphorylation
Similarly to that in yeasts and animals, the ac-
tivity of plant CDK/cyclin complexes is regu-
lated by phosphorylation/dephosphorylation
and the interaction with regulatory proteins.
Yeast CDK/cyclin complexes are subject to an
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CKIs:cyclin-dependentkinase inhibitors
inhibitory phosphorylation of an N-terminal
Tyr residue in the CDK partner, whereas
in vertebrates CDKs are phosphorylated on
both an N-terminal Tyr and Thr residue. Tyrphosphorylation is catalyzed by the WEE1 ki-
nase, and both Tyr and Thr phosphorylation
is counteracted by the dual-specificity phos-
phatase CDC25.
Tyr phosphorylation of A-type CDK has
been detected unambiguously and shown
to down-regulate CDKA activity under cy-
tokinin deprivation, osmotic stress, or DNA
damage (158,210; D.I. & L.D.V., unpublisheddata). The inhibitory phosphorylation sites
are also conserved in B-type CDKs, but bio-
chemical evidence for CDKB phosphoryla-
tion is still lacking, the only known exception
being the picoeukaryote O. tauri, in which
CDKB, but not CDKA, is phosphorylated
on Tyr upon activation of the DNA integrity
checkpoint (31, 57).
Plants possess a WEE1 kinase that is puta-tively involved in the inhibitory phosphoryla-
tion of CDKs (167, 176, 186; D.I. & L.D.V.,
unpublished results). Overexpression of the
maize (Zea mays) or Arabidopsis WEE1 genes
inS. pombecauses cell cycle arrest (167, 176),
although its in planta inhibitory effect on the
cell cycle remains to be proven.
Recently, in the primitive unicellular al-gae, O. tauri, a bona fide CDC25 has been
found (97) that presumably controls the activ-
ity of the B-type CDK (57). However, inAra-bidopsis,rice,and Chlamydomonas,whoseentire
genome sequences are available, no CDC25
gene encoding a CDK-activating phosphatase
could be identified (11, 186). Nevertheless,
biochemical and genetic evidence suggest that
higher plants also have a phosphatase thatcan activate CDK/cyclin complexes; for in-
stance, inactive CDK/cyclin complexes puri-
fied from cytokinin-starved and G2-arrested
tobacco cells can be activated in vitro by the
yeast CDC25 (210). Furthermore, overex-
pression of theS. pombe cdc25gene in trans-
genic tobacco andArabidopsisplants promotes
mitosis (10, 120, 134, 204, 209). In general,overexpression of the S. pombe cdc25mimics
the developmental effect caused by cytokinin
(174), in agreement with the pivotal role o
cytokinins for the G2-to-M transition in tobacco cells (107, 210).
Recently, an Arabidopsis gene has been
identified that encodes a CDC25-like pro
tein, capable of binding a phosphothreo
nine 14/phosphotyrosine 15 peptide and o
activating ArabidopsisCDK activity in vitro
(105). However, unlike the classical CDC25s
this CDC25 lacks the important N-termina
regulatory domain. Additionally, Arabidopsi
CDC25cannot complement yeastcdc25mu
tants and does not affect the cell cycle when
overexpressed or knocked-down in plant
(D.I. & L.D.V., unpublished data). The plan
CDC25 protein also displays similarity with
the yeast Arsenate [As(V)] reductase and, cor
respondingly, has recently been demonstrated
to possess reductase As(V) activity. Moreover
its overexpression improves the tolerance otransgenic Arabidopsis plants to mildly toxi
levels of As(V), whereas its knockout increased
As(V) sensitivity (13). As such, it is unlikely
that theArabidopsis CDC25-like gene encode
a true otholog of the classical CDC25, bu
rather has a function totally unrelated to cel
division.
Cyclins are also subject to phosphorylation. The tobacco D cyclin CYCD3;3 is phos
phorylated on Thr191, and this phosphoryla
tion is required for nuclear localization and
maximum kinase activity (129). In vivo phos
phorylation of the ArabidopsisCYCD3;1 oc
curs when cells are sucrose starved (136).
CDK Inhibitors
Cyclin-dependent kinase inhibitors (CKIsregulate cell cycle progression by binding an
inhibiting CDKs (127). Budding yeast ha
three CKIs: Far1p inhibits G1 CDK activ
ity; Sic1p controls S-phase entry by regulat
ing G1/S CDK complexes; and Pho81p in
activates a CDK/cyclin complex that play
a role in regulating gene expression un
der low-phosphate conditions. The situation
in fission yeast (Schizosaccharomyces pombe) i
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considerably simpler because only one CKI,
designated Rum1, is known to control mitotic
CDK complexes. Mammals have seven CKIs,
which are subdivided into two very differentclasses. The INK4 family proteins contain an
ankyrin repeat and selectively inhibit the G1
CDKs, CDK4 and CDK6. The Cip/Kip fam-
ilyofCKIscomprisesp21 Cip1 (also called Sdi1,
Waf1, or CAP20), p27Kip1, and p57Kip2, all
of which have a conserved domain at the N
terminus. The Cip/Kip CKIs inhibit a broad
range of CDK/cyclin complexes involved in
the control of both G1-to-S and G2-to-M(131).
The first plant CKIs have been character-
ized in a yeast two-hybrid screen for CDKA-
interacting proteins (40, 89, 112, 194, 211).
Additional plant CKIs have been identified
in silico through genome data mining (30,
40). The specific interaction of ICK2/KRP2
with CDKA has also been confirmed in vivo
(188). Plant CKIs have a peculiar struc-ture: They all share a C-terminally located
31-amino-acid domain. This conserved do-
main is involved in binding CDKs and cy-
clins and is essential for the inhibitory ac-
tivity of the proteins (30, 40, 88, 89, 112,
157, 194, 212). Because of its similarity with
the N-terminally located CKI domain of the
mammalian Cip/Kip proteins, plant CKIsare most commonly known as Kip-RelatedProteins or KRPs, although the two found-
ing members are also known as Interactors
of Cdc2 Kinase or ICK (40, 112, 194). Ara-bidopsis encodes seven ICKs/KRPs, denom-
inated ICK1/KRP1, ICK2/KRP2, KRP3,
KRP4, KRP5, KRP6, and KRP7. All seven
ICKs/KRPs also interact with D cyclins
(CYCD1, CYCD2, and CYCD3) (40, 112,195, 211). Proof of in vivo binding speci-
ficity between plant ICKs/KRPs and D-type
cyclins is that the cell division inhibitory
activity caused by ICK/KRP overexpression
(see below) can be complemented by co-
overexpression of D-type cyclins (89, 157,
212). Monocotyledonous ICKs/KRPs might
differ slightly in their biochemistry from their
dicotyledonous counterparts, because maize
ICKs/KRPs:inhibitors of plantCDKs
ICKs/KRPs inhibit both A- and D-type cy-
clin/CDK complexes (30).
Length and primary structure of the
N-terminal part are highly variable withinICKs/KRPs of a single plant species (40). A
functional analysis of ICK1/KRP1 indicates
that the N-terminal domain contains a se-
quence that decreases the protein stability in
vivo. Possibly, such a sequence could drive the
temporal selective degradation of ICK/KRP
proteins at different time points in the cell cy-
cle (157, 195, 212). In accordance with a role
for proteolysis as an important mechanism tocontrol ICK/KRP activity, the ICK2/KRP2
levels have been shown to be controlled by
the proteasome (188). So far, no INK-type
inhibitors have been found in plants, in agree-
ment with the absence of the known INK sub-
strates (at least in mammals) being CDK4-
and CDK6-related CDKs.
The RBR/E2F/DP Pathway
Despitethe billion years of evolution that sep-
arate animals from plants, both types of or-
ganisms use the same Rb/E2F/dimerization
partner (DP) pathway to control the G1-
to-S transition. In the two cases, Rb pro-
teins interact with the E2F/DP complex to
repress transcription of E2F-regulated genes
(50, 144, 160). Even the canonical DNA se-quence (TTTCCCGC) recognized by the
E2F/DP transcription factors of animals and
plantsisidentical(2,102).Thisidentityargues
infavorofthehypothesisthattheRb/E2F/DP
pathway had already evolved in primitive or-
ganisms, before the branching between ani-
mal and plant taxa. However, whereas Ara-
bidopsisencodes multiple CDKs, cyclins, andKRPs, its genome contains only one Rb-
relatedgene (RBR). All known plant RBR pro-
teins have, like their animal counterpart, two
blocks of conserved sequences that form the
so-called A/B pocket domain (1, 49, 72, 205),
which is the docking place for the E2F tran-
scription factors.
In animals, Rb is phosphorylated by
CDK4/CYCD, CDK6/CYCD, CDK2/
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Megagametophyte:the femalegametophyte, whichdevelops from amegaspore
CYCE, and CDK2/CYCA complexes at
the G1-to-S transition. A PP1 phosphatase
dephosphorylates Rb at G2/M. Much less is
known about the kinases and phosphatasesthat govern the plants RBR phosphorylation
state. Plant RBR proteins interact with D
cyclins through a conserved LxCxE motif at
the N terminus of the latter (1, 34, 84, 129,
130, 165). The plant RBR-associated kinase
complex contains CDKA and a D cyclin (14,
101, 129) (Figure 1). Phosphorylation of
plant RBR proteins by CDKs depends on the
cell cycle phase (55, 129).
ArabidopsisRBR knock-outs are sterile, be-
cause they fail to arrest the mitotic divisions
in the mature female megagametophyte be-
fore fertilization, resulting in excessive nu-
clear divisions in the embryo sac. In addi-
tion, the central cell nucleus, which gives rise
to the endosperm after fertilization, initiates
autonomous endosperm development. These
data indicate that RBR controls the arrestof the mature unfertilized megagametophyte
(51). Analogously, RBR regulates the differ-
entiation of root stem cells (202).
Whereas in dicots the cell cycle and post-
cell cycle-related functions of RBR appear to
be performed by a single RBR gene, mono-
cotyledonous species possess two types of
RBR genes. In maize, two RBR proteinshave a complementary accumulation pattern:
RBR3 is exclusivelypresent during themitotic
phase of endosperm development, whereas
RBR1 is mainly observed post-mitotically
in endoreduplicating and differentiating cells
(152). These data suggest a division of labor,
whereby RBR3 participates in cell cycle con-
trol and RBR1 in cell differentiation.
Rb proteins control the activity of the ade-novirus E2 promoter-binding factor (E2F)
family of transcription factors that, in turn,
control the expression of many genes required
for entry into and execution of S phase and
cell cycle progression (3, 12, 46, 170). Ara-
bidopsiscontains six E2Fs (E2Fa, E2Fb, E2Fc,
E2Fd/DEL2, E2Fe/DEL1, and E2Ff/DEL3)
and two DPs (DPa and DPb). E2Fa and E2Fbact as transcriptional activators as illustrated
by their ability to induce reporter genes har
boring the E2F consensus cis-activating el
ement (102, 118, 171). Moreover, transienoverexpression ofE2FaandDPainduces qui
escent mesophyll cells to re-enter S phase
(150), whereas ectopic co-expression ofE2Faand DPa induces sustained cell proliferationin
differentiated cotyledon and hypocotyl cell
(39, 103, 150). Also co-expression of E2F
with DPa stimulates cell division, resulting
in shortening of the cell cycle (115). By con
trast, E2Fc, which lacks a strong activationdomain, operates as a negative regulator o
the E2F-responsive genes (42, 102, 118, 150
(Figure 1) and, consequently, its overexpres
sion inhibits cell division (42).
In mammals, numerous E2F target gene
are well characterized. These genes encod
proteins active during DNA replication, mi
tosis, DNAcheckpoint control, apoptosis, an
differentiation (46). By contrast, only a fewplant E2F targets have been validated experi
mentally, including MCM3, CDC6, CDT1aPCNA, RBR, and RNR (26, 27, 37, 39, 53
54, 102, 142, 152, 171). In silico analysis o
the Arabidopsisgenome for the presence o
the TTTCCCGCC canonical motif identi
fied 183 putative E2F target genes, includ
ing genes involved in DNA replication andcell cycle regulation (142). A more profoun
analysis using microarray data and bioinfor
matics tools allowed the identification of 70
putativeE2F targetgenes conserved overAra
bidopsisand rice. These genes encode protein
involved in cell cycle regulation, DNA repli
cation, and chromatin dynamics. In addition
several genes have been identified with po
tentially novel roles in the regulation of the Sphase (187).
E2Fs and DPs contain only one DNA
binding domain and, therefore, requir
dimerization to interact with the canonica
E2F motif (2, 102, 114, 141). By contrast
E2Fd/DEL2, E2Fe/DEL1, and E2Ff/DEL3
proteins are atypical E2F factors becaus
they contain two DNA-binding domainthat allow them to bind as a monome
in a DP-independent manner to the E2F
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DNA-binding sequence. Additionally, these
proteins do not contain a transactivation do-
main and, as such, might play a role in a neg-
ative feedback loop to repress E2F-activatedpromoters (118, 186) (Figure 1). The atyp-
ical E2F/DEL proteins lack an Rb-binding
motif. Only very recently have two mam-
malianhomologs,designatedE2F7 andE2F8,
been discovered (28, 36, 45, 110, 117), high-
lighting that cell cycle research in plants can
yield novel insights into cell cycle research in
animals.
The biphasic expression pattern of
E2Fe/DEL1during the cell cycle, with tran-
scripts peaking at the G1-to-S and G2-to-M
transition points, while absent during S
phase (118), suggests that E2Fe/DEL1 might
control the temporal expression of E2F
target genes. E2Ff /DEL3 overexpression in
Arabidopsisreduces the size of differentiated
cells in roots and hypocotyls, whereas cells
with reduced E2Ff /DEL3 levels are larger,especially in the hypocotyls. These effects
of E2Ff/DEL3 are not associated with
changes in the nuclear ploidy levels or in
the expression of cell cycle genes. However,
expression of a subset of cell wall biogenesis
genes is misregulated in an E2Ff/DEL3-
dependent manner and, based on chromatin
immunoprecipitation experiments, theseseem to be direct E2Ff/DEL3 targets (143).
In contrast to E2Ff/DEL3, E2Fe/DEL1
plays an important role in the control of
endoreduplication (see below).
CELLULAR VERSUSORGANISMAL THEORY
The role of the cell cycle machinery in plantdevelopment has been subject to debate. Ob-
viously, cell division is essential in generating
the cells that constitute tissues and organs.
However, whether cell division is the driver
of growth and development (the cellular the-
ory) or, alternatively, cell division merely fol-
lows a developmental plan (the organismal
theory) is more difficult to answer. Basically,
to what extent do oriented cell divisions con-
tribute to the determination of form? Exper-
iments in the late 1950s and early 1960s sug-
gested that cell division has little function in
growth and morphogenesis. Seedlings fromheavily-irradiated wheat (Triticum aestivum)
grains grow to some extent without negligible
cell division and resemble untreated seedlings
in many aspects of metabolism (74), growth
(73, 75), and maturation of cells present in the
embryo (59). A 10-day-old -irradiated wheat
seedling is as large as a 3-day-old unirradiated
seedling, but contains threefold and 8.5-fold
fewer, albeit much larger, epidermal and mes-ophyll cells, respectively (73). Habers work
provided the first experimental evidence that
genetic information specifies leaf form inde-
pendently of the extents and orientations of
cell divisions.
Thanks to the ability to alter cell cycle pa-
rameters in transgenic plantsthe longstanding
question on the importance of cell division indetermining organ size and shape has been re-
addressed recently. In agreement with Habers
work (59, 7375), at least for leaves, develop-
ment seems to follow the concept laid down in
the organismal theory. Transgenic Arabidop-
sisplants constitutively overproducing any of
the ICKs/KRPs have smaller leaves that con-
sist of tenfold fewer cells with sixfold greater
average size than control cells. The reduc-tion in cell number is thus compensated for
by an increased cell size (40, 89, 196). Also in
rice,OsKRP1overexpression causes a reduc-
tion in cell number that is compensated for
by an increased cell size (D.I. & L.D.V., un-
published data). Similarly, overexpression of a
dominant negative CDKA or a nondegradable
CYCB1;1 in tobacco retards the cell cycle andcauses the formation of larger cells (78, 199).
On the other hand, constitutive overexpres-
sion of positive regulators of the cell cycle,
such asE2Fa,CYCA3;2, orCYCD3;1, results
in more cells (39, 43, 208). Here, the increase
in cell number is compensated for by a de-
crease in cell size. All these observations sup-
port the organismal theory of plant develop-
ment in which the size and shape of an organor organism is set to some extent by a certain
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endogenous mechanism independently of cell
division processes (96). The phenomenon by
which cell numbers is inversely correlated to
cell size is called compensated cell enlarge-ment (181). Also in animals, cell division
and cell expansion can compensate each other
to achieve an optimal species-specific organ
size (35, 139). InDrosophila melanogaster, this
phenomenon is also known as the total mass
checkpoint (139).
It is not known what determines the
blueprint for leaf shape and size, but hor-
monal gradients probably play an importantrole. However, not all experimental data fit
the organismal theory. For example, overex-
pression of a dominant negative CDKA un-
der the control of a seed-storage promoter
deregulates embryo development (79). Fur-
thermore, overexpression ofCYCB1;1under
the control of theCDKA;1promoter acceler-
ates growth of roots, as would be expected un-
der the cellular theory (47). Previously, we hadproposed that these two theoriesthe cellu-
lar and the organismalare too polarized (9).
Rather, cell division, cell differentiation, and
morphogenesis can be considered as integral
parts of a higher-level ontogenetic program
defined by both short-range and long-range
signaling between growth zones (9). The fu-
ture challenge is to elucidate how the devel-opmental signaling components interact with
the cell cycle machinery in animals and plants.
ENDOREDUPLICATION
The normal cell cycle mode is characterized
by a round of DNA replication (S phase) fol-
lowed by mitosis and cytokinesis (M phase).
Two gap phases (G1 and G2) usually separatetheSandMphases.However,manyplantcells
have a different cell cycle mode with cells un-
dergoing iterative DNA replications without
any subsequent cytokinesis. This endoredu-
plication is frequently observed in some, but
not all, plants (20, 33, 38, 66, 128, 175, 180).
The level of ploidy varies between species
and tissues. In Arabidopsis, nuclei with up to
32C are detected (66), but some maize en-
dosperm cells attain a DNA content as high
as 96C or 192C (104, 109). The physiologi
cal role of endoreduplication is subject to de
bate, and several hypotheses have been proposed. Endoreduplication probably plays an
important role in the differentiation proces
of postmitotic cells because the onset of th
endocycle often characterizes the switch be
tween cell proliferation and differentiation
as observed during hypocotyl elongation, tri
chome growth, andfruit andleaf developmen
(7, 17, 95, 99, 106). In addition, plant specie
that endoreduplicate are often characterizedby a rapid life cycle and improved yield sta
bility, implying that endoreduplication migh
support fast development (5). Endoredupli
cation was long believed to be essential to
support cell growth and to maintain an opti
mal balance between cell volume and nuclear
DNA (61, 82, 83, 122, 180). However, thi
concept is currently being challenged (175)For example, cell size and overall ploidy leve
are not correlated in root cells of differen
Arabidopsisecotypes (8). Similarly, recent ex
periments in which the level of endoredupli
cation is modified do not support this hy
pothesis. For example, high overexpression o
ICK/KRPgenes causes a remarkable overal
decrease in the ploidy level but, at the same
time, greatly increases cell size (40, 89, 211)Also, cell size of the starchy endosperm did
not change dramatically when the endoredu
plication process in the maize endosperm wa
specifically inhibited by overexpression of a
dominant negative allele of the CDKA gen
(109). An alternative hypothesis is that muta
tions, which plants accumulate during thei
sessile life, are buffered by endoreduplication. Indeed, many plants are exposed dur
ing their life cycle to less favorable condi
tions, and the various copies, such as 8, 16
32, 64, etc., of the genome would safeguard
that the genome retains functional copies
Another hypothesis is that endoreduplication
is important to maintain an optimal balanc
between organellar and nuclear DNA. Ad
ditionally, endoreduplication might enhancthe metabolic capacity of plant cells. Thi
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hypothesis is based on the high polyploidy of
the endosperm cells of cereal seeds. An in-
crease in the gene copy numbers of metabolic
genes might allow the endosperm cells to syn-thesize very large amounts of storage prod-
ucts, such as starch and storage proteins (90,
99, 106, 180). In favor of this hypothesis,
genome amplification of maize endosperm
cells coincides with cell enlargement and the
onset of starch and protein accumulation.
However, recent experiments argue against
a role of endoreduplication in enhancing
metabolic activity, because by overexpressionof the dominant negativeCDKAin the maize
endosperm, starch and protein accumulation
were only slightly reduced as a consequence
of the decrease in the endoreduplication level
(109).
How are cells triggered to undergo en-
doreduplication? InArabidopsis, the exit of the
mitotic cycle correlates with the onset of en-
doreduplication, suggesting that this processcan be perceived as a continuum of the mi-
totic cell cycle in which mitosis, but not DNA
replication, is inhibited (87). In the maize en-
dosperm, the tomato (Lycopersicon esculentum)
fruit, and theArabidopsisleaf, the onset of en-
doreduplication coincides with a decrease in
M phasespecific CDK activity (7, 17, 71, 95,
106). In S. pombe andin D. melanogasterinhibi-tion of the M phaseassociated CDK activity
issufficienttodrivecellsintotheendoredupli-
cation cycle (52, 76, 153). As such, it is reason-
able to believe that in plants too an active pro-
cess controls the decrease in M-phase CDK
activity. Over the past few years, considerable
progress has been made in understanding the
molecular basis of endoreduplication in plants
(Figure 3). The mitotic cycle and endocyclehave DNA replication in common, and both
cell cycle modes probably make use of the
same machinery. In agreement, constitutive
overexpression of genes that stimulate DNA
replication has been shown to promote both
the mitotic cell cycle and the endocycle (23,
39, 103, 155). Thus, the difference between
the mitotic cycle and the endocycle must belooked for in the mechanism regulating the
MIF:mitosis-inducingfactor
G2-to-M transition. The decision of a cell to
either undergo endoreduplication or continue
mitosis might depend on a cellular factor, des-
ignatedMitosis-Inducing Factor (MIF) (39), a
hypothesis based on extensive ectopic cell di-visions in some tissues (such as root cap) and
extensive endoreduplication in other tissues
(such as root cortex)caused by the overexpres-
sion of bothE2Faand DPa. The ectopic cell
division phenotype has mostly been observed
in the proximity of stomata that are known to
be able to divide. Possibly, the cells in which
E2Fa-DPaoverexpression triggers additionalcell division might possess a MIF that is inac-
tive or absent in the endoreduplicating cells.
Sorting cell types in whichE2Fa-DPahas dif-
ferent effects and comparing their transcrip-
tome should help in unraveling the nature of
MIF. A likely candidate to be part of MIF is the
CDKB1;1 kinase whose role in the mitosis-
to-endocycle switch has been hinted by its
temporal expressionpattern duringleaf devel-opment. CDKB1;1 is highly expressed in di-
viding cells and is down-regulated at the onset
of endoreduplication. In concert, transgenic
plants overproducing a dominant negative
CDKB1;1 undergo increased endoreduplica-
tion. When the dominant negative CDKB1;1
is co-expressed with the heterodimeric tran-
scription factor E2Fa-DPa, the endoredupli-cation phenotype is enhanced, whereas the
extra mitotic cell divisions normally induced
by ectopicE2Fa-DPa expression are repressed
(17). Thus, CDKB1;1 activity seemingly con-
trols the balance between mitotic cell divi-
sion and endoreduplication. Candidate cy-
clin genes that act together with CDKB1;1
are CYCA3;2, CYCA2;3, and CYCD3;1, as
they inhibit the endoreduplication processupon their overproduction (43, 85, 208). Also
the cyclin CYCB1;2 is a possible candidate,
as illustrated by its ectopic expression that
changes the developmental fate of trichome
cells from endocycling into mitotically divid-
ing cells (156).
Recently, the ICKs/KRPs have been
demonstrated to contribute to the control ofthe mitosis-to-endocycle transition. Whereas
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CDKB
CYCA/BCYCA/B
WEE1
DEL1
CCS52
KRP
CDKA
CYC
Destruction
Destruction
?
?
P
?
DK
CYCA/B
KRPWEE1
DEL1
CCS52
P
CDKA
CYC
Destruction
Destruction
?
?
?
E2Fa b
ba
High CDKAactivity
Low CDKAactivity
Mitotic cell cycle Endoreduplication cycle
DP
E2Fa/b
Figure 3
Schematic overview of the mitosis-to-endocycle transition. (a) Mitotic cell cycle. (b) Endoreduplication
cycle. Colored and gray-shaded symbols correspond to active and inactive molecules, respectively.Mitotically dividing cells are characterized by high CDKA/CYC and CDKB/CYC activities. B-typeCDKs, of which some family members are under transcriptional control of the E2F pathway, prevent theinhibition of the CDKA/CYC complexes through phosphorylation of the CDK inhibitory ICK/KRPproteins, triggering their destruction. Exit from the mitotic cell cycle is also negatively regulated by theatypical E2F-like E2Fe/DEL1 transcription factor, in a manner yet to be determined, and isaccompanied with the activation of the CCS52 protein that probably targets B-type CDK-associatedcyclins for destruction. The decrease in B-type CDK activity will result in a stabilization of theICK/KRP proteins, which, in turn, will down-regulate the activity of the CDKA/CYC complexes. TheWEE1 kinase might also be partly responsible for the decrease in CDKA/CYC activity. The decrease inCDKA/CYC activity results in inhibition of mitosis, but still allows DNA replication to occur withendoreduplication as a consequence.
high ICK2/KRP2 levels repress both cell di-
vision and endoreduplication, weak overex-
pressioninhibitsthemitoticcellcyclespecific
CDKA complexes only, resulting in a pre-
mature onset of the endoreduplication pro-
gram (188). A similar dose-dependent ef-
fect on the cell cycle has been observed for
ICK1/KRP1 (201). The difference in sensi-tivity of CDK complexes toward ICK2/KRP2
inhibitionmightbecausedbythenatureofthe
cyclins in complex with CDKA at either theG1-to-S or the G2 phases (188).
The abundance of the ICK2/KRP2 pro-
tein is developmentally regulated and con-
trolled through CDK phosphorylation and
proteasome-dependent degradation. Its ac-cumulation in plants overexpressing a dom-
inant negative allele of CDKB1;1 strongly
suggests that this particular CDK target
ICK2/KRP2 for degradation by phosphory
lation. In this model, the CDKB1;1 kinase
inhibits ICK2/KRP2 activity, resulting in
higher CDKA activity at the G2-to-M transi
tion and consequently less endoreduplication
(188) (Figure 3).At this stage, the possibility that th
CDKB1;1 kinase suppresses the endocycl
alsovia other mechanisms cannotbe excludedIn fission yeast, the mitotic CDK complex ha
been demonstrated to prevent the relicens
ing of replicated DNA by its association with
the replication complex during chromosom
duplication, preventing reinitiation of DNAsynthesis (203). Similarly, CDKB1;1 migh
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negatively regulate pre-replication complex
assembly and thereby influence the progres-
sion of endocycles as well as the mitosis-to-
endocycle progression. In concert with thishypothesis, and despite its anticipated role
during mitosis, CDKB1;1 transcripts and as-
sociated protein activity can already be de-
tected during S-phase progression (18, 124,
138, 168). Actually, the kinetics ofCDKB1;1
transcription during S phase are identical to
those of genes that encode the pre-replication
complex itself (such as MCMs and CDC6).
The reason could be that CDKB1;1 pro-moter activity is controlled by E2F activity,
as shown by its up-regulation in E2Fa/DPa-
overexpressing plants and mutational analysis
of the E2F-binding site in theCDKB1;1pro-
moter (17, 115) (Figures 2and3).
Another well-documented molecular
switch for the mitotic cycle to the endocycle
is the CCS52A protein. InM. sativa, expres-
sion ofCCS52 correlates with the onset ofendoreduplication, and down-regulation of
CCS52A expression significantly reduces the
ploidy level (25, 178, 190). Mitotic cyclins
are likely candidates of CCS52A-mediated
proteolysis (64, 98). We hypothesize that the
cyclin partner of CDKB1;1 is the target for
CCS52A-mediated proteolysis (Figure 3).
Mitotic CDK activity could also be negativelyregulated by WEE1, because in the maize en-
dosperm theWEE1transcript levels increase
when cells undergo endoreduplication (176).
Through a still unspecified molecular
mechanism, E2Fe/DP-E2F-like protein 1
(DEL1) also regulates the onset to en-
doreduplication (191). Loss of function ofE2Fe/DEL1 results in increased ploidy levels,
whereas ectopic expression ofE2Fe/DEL1re-
duces endoreduplication. The observed DNA
ploidy changes are correlated with altered ex-
pression of a subset of E2F target genes that
encode proteins necessary for DNA replica-
tion. BecauseE2Fe/DEL1transcripts are de-
tected exclusively in mitotically dividing cells,the E2Fe/DEL1 operates as an important in-
hibitor of the endocycle onset by preserving
the mitotic state of proliferating cells and bysuppressing transcription of genes that are re-
quired for cells to enter the DNA endoredu-
plication cycle (191) (Figure 3).
CONCLUDING REMARKS
Considerable progress has been made in re-
cent years in our knowledge of the basicmechanisms that regulate cell division and en-
doreduplication in higher plants. In contrast,
very little is known on how the cell cycle ma-
chinery communicates with both intrinsic de-
velopment signals and external cues. Under-
standing this process might help to explain
growth rates and architecture of plants. Fur-
thermore, it might open new perspectives in
the breeding or engineering of plants with im-proved yield.
SUMMARY POINTS
1. The cell cycle machinery of plants is regulated by components that are conserved in
other eukaryotes as well as by molecules that are plant specific.
2. Plants contain many more cyclins than animals, possibly reflecting their role in ren-
dering plant development very plastic.
3. Plants are particularly well suited to study how the cell cycle machinery is regulated
by intrinsic developmental signals and environmental cues.
4. An increase in cell number in leaves is compensated for by a decrease in cell size and
vice versa.
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5. Endoreduplication results from a controlled down-regulation of cyclin-dependentkinase activity at the G2-to-M transition. Various mechanisms can account for this
down-regulation.
ACKNOWLEDGMENTS
The authors thank Aurine Verkest for critical reading of the manuscript, Martine De Cock fo
help preparing it, and Karel Spruyt for artwork. This work was supported by a grant from th
Interuniversity Poles of Attraction Program-Belgian Science Policy (P5/13) and the Research
Foundation-Flanders (grant no. G008306). L.D.V. is a Postdoctoral Fellow of the Research
Foundation-Flanders.
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