cell division, cell growth, cell cycle
DESCRIPTION
Cell division, cell growth, cell Cycle. MEIOSIS I: Separates homologous chromosomes. INTERPHASE. PROPHASE I. METAPHASE I. ANAPHASE I. Sister chromatids remain attached. Centromere (with kinetochore). Centrosomes (with centriole pairs). Chiasmata. Metaphase plate. Sister chromatids. - PowerPoint PPT PresentationTRANSCRIPT
Cell division, cell growth, cell Cycle
• Interphase and meiosis I
Centrosomes(with centriole pairs)
Sisterchromatids
Chiasmata
Spindle
Tetrad
Nuclearenvelope
Chromatin
Centromere(with kinetochore)
Microtubuleattached tokinetochore
Tertads line up
Metaphaseplate
Homologouschromosomes
separate
Sister chromatidsremain attached
Pairs of homologouschromosomes split up
Chromosomes duplicateHomologous chromosomes
(red and blue) pair and exchangesegments; 2n = 6 in this example
INTERPHASE MEIOSIS I: Separates homologous chromosomes
PROPHASE I METAPHASE I ANAPHASE I
Figure 13.8
1. Synapsis (聯會 )(synaptonemal complex)
2. cross over
TELOPHASE I ANDCYTOKINESIS
PROPHASE II METAPHASE II ANAPHASE II TELOPHASE II ANDCYTOKINESIS
MEIOSIS II: Separates sister chromatids
Cleavagefurrow Sister chromatids
separate
Haploid daughter cellsforming
During another round of cell division, the sister chromatids finally separate;four haploid daughter cells result, containing single chromosomes
Two haploid cellsform; chromosomesare still doubleFigure 13.8
• Telophase I, cytokinesis, and meiosis II
MITOSIS MEIOSIS
Prophase
Duplicated chromosome(two sister chromatids)
Chromosomereplication
Chromosomereplication
Parent cell(before chromosome replication)
Chiasma (site ofcrossing over) MEIOSIS I
Prophase I
Tetrad formed bysynapsis of homologouschromosomes
MetaphaseChromosomespositioned at themetaphase plate
Tetradspositioned at themetaphase plate
Metaphase I
Anaphase ITelophase I
Haploidn = 3
MEIOSIS II
Daughtercells of
meiosis I
Homologuesseparateduringanaphase I;sisterchromatidsremain together
Daughter cells of meiosis IIn n n n
Sister chromatids separate during anaphase II
AnaphaseTelophase
Sister chromatidsseparate duringanaphase
2n 2nDaughter cells
of mitosis
2n = 6
• A comparison of mitosis and meiosis
Cell cycle:
--- the life of a cell from the time it is first formed from a dividing parent cell until its own division into two cells. Smallest unit of life
all living things must reproduce Cells replicate for growth, replacement, and repair
Cell division functions in reproduction, growth, and renewal.
20 µm200 µm
Cell CycleThe Cell’s Time Clock
• Cell division requires Mitosis & Cytokinesis
• Phases of a dividing cell’s life – interphase
• cell grows• replicates chromosomes• produces new organelles &
biomolecules– mitotic phase
• cell separates & divides chromosomes
– mitosis• cell divides cytoplasm &
organelles– cytokinesis
Cytokinesis
MMitosis
G1Gap 1
G0Resting
G2Gap 2
SSynthesis
Cell cycle MMitosis
G1Gap 1
G0Resting
G2Gap 2
SSynthesis
• Cell has a “life cycle”cell is formed from a mitotic division
cell grows & maturesto divide again
cell grows & matures to never divide again
G1, S, G2, M G0
epithelial cells,blood cells,stem cells
brain nerve cells
liver cells
Interphase• Cell performs normal function
• Three subphases:– G1: cell duplicates most organelles– S: quantity of DNA in the cell is
doubled as chromosomes are replicated. Each chromosome has a pair of sister chromatids connected by a centromere that contains a kinetochore
– G2: chemical components stockpiled
• Nucleolus present
Mitosis
• Nuclear division without a reduction in chromosome number
• Each new cell (daughter cell) will have the same quantity of DNA as the parental cell
• Why is this important?
• Mitotic events can be categorized into discrete stages based on what is happening to structure of the cell
• Stage include:– Prophase
• Prometaphase– Metaphase– Anaphase– Telophase
Prophase(Including Prometaphase)
• Pro• Three things visibly
occur– Chromosomes condense
(shorten)– Centrosomes migrate to
the poles while producing spindle fibers
– Nuclear membrane fragments
Metaphase
• Meta• Chromosomes are
moved by growing spindle fibers to the equator of the cell (metaphase plate)
• Centrosomes are at the poles, nuclear membrane is gone
Metaphase Plate
Anaphase
• Ana• Centromere splits into two• Spindle fibers shorten from
kinetochore end separating sister chromatids
• Activated kinetochores “pull” chromatids along the spindle fibers and toward the poles
Telophase
• Telo• Nuclear membrane
reforms around each region of chromosomes
• Nucleolus reforms• Cytokinesis (division
of the cytoplasm) may occur
Cytokinesis May Vary Between Major Taxonomic Groups
Cytokinesis divides the cytoplasm
* Cleavage furrow * No cleavage furrow
Actin +Myosin
Daughter cells
1 µmVesiclesforming cell plate
Wall of patent cell Cell plate New cell wall
(b) Cell plate formation in a plant cell (SEM)
Cleavage furrow
Contractile ring of microfilaments Daughter cells
100 µm
(a) Cleavage of an animal cell (SEM)
2006-2007
Regulation of Cell Division
Coordination of cell division
• A multicellular organism needs to coordinate cell division across different tissues & organs– critical for normal growth,
development & maintenance• coordinate timing of
cell division• coordinate rates of
cell division • not all cells can have the
same cell cycle
• How do cells know when to divide? – cell communication signals
• chemical signals in cytoplasm give cue• signals usually mean proteins
– activators– inhibitors
Activation of cell division
experimental evidence: Can you explain this?
G2
S G1
M
metaphaseprophase
anaphasetelophase
interphase (G1, S, G2 phases)mitosis (M)cytokinesis (C)
C
• Frequency of cell division varies by cell type– embryo
• cell cycle < 20 minute– skin cells
• divide frequently throughout life• 12-24 hours cycle
– liver cells• retain ability to divide, but keep it in
reserve• divide once every year or two
– mature nerve cells & muscle cells• do not divide at all after maturity• permanently in G0
Frequency of cell division
Overview of Cell Cycle Control
• Two irreversible points in cell cycle– replication of genetic material– separation of sister chromatids
• Checkpoints – process is assessed & possibly halted
centromere
sister chromatids
single-strandedchromosomes double-stranded
chromosomes
There’s noturning back,now!
Cell Cycle Regulation
• Cell cycle events are triggered by the cell-cycle control system; a set of molecules found in the cytoplasm affected by internal and external controls
• Checkpoints in G1, G2, and M phases of the cycle• G1 checkpoint is most critical. May throw cells
out of cyclic phase into G0, never to divide again
Other Internal and External Factors
• Internal – M checkpoint does not proceed until signal is received that all
kinetochores are attached to spindle microtubules
• External– Growth factors: cycle will not proceed if requirements are not met– Social signals
• Density-dependent inhibition: under crowded conditions chemical requirements are insufficient to allow cell growth
• Anchorage dependence: some cells must be attached to a substrate in order to replicate
– DNA damage inhibits growth
External signals: ex. Growth factors
~ Cells fail to divide if an essential nutrient is left out of the culture medium.~ GFs trigger a signal transduction pathway that allows the cells to pass the G1 checkpoint and divide.
cell
PDGF receptor
Signal transduction
Cell division
PDGF
External signals
• Growth factors– coordination between cells– protein signals released by body cells
that stimulate other cells to divide• density-dependent inhibition
– crowded cells stop dividing– each cell binds a bit of growth factor
» not enough activator left to trigger division in any one cell
• anchorage dependence – to divide cells must be attached to a
substrate» “touch sensor” receptors
Density-dependent inhibition of cell division
~ Crowded cells stop
dividing
single layer
External signals: physical factor
Cells anchor to dish surface anddivide (anchorage dependence).
When cells have formed a complete single layer, they stop dividing (density-dependent inhibition).
If some cells are scraped away, the remaining cells divide to fill the gap and then stop (density-dependent inhibition).
25 µm
Anchorage dependence
• Most animal cells exhibit anchorage dependence– In which they must be attached to a substratum to divide
* Cancer cells: ~ Exhibit neither density-
dependent inhibition nor anchorage dependence
25 µm
Cancer cells do not exhibit anchorage dependence or density-dependent inhibition.
25 µm
Normal cell ~ single layer
E2F
nucleuscytoplasm
cell division
nuclear membrane
growth factor
protein kinase cascade
nuclear pore
chromosome
Cdkcell surfacereceptor
P
PP
P
P
E2FRb
Rb
Growth factor signals
Internal signal of a Growth Factor
• Platelet Derived Growth Factor (PDGF)– made by platelets in blood clots– binding of PDGF to cell receptors stimulates cell
division in fibroblast (connective tissue)• heal wounds
Don’t forgetto mentionerythropoietin!(EPO)
The sequential events of the cell cycle are directed by a distinct cell cycle control system, a cyclically operating set of molecules in the cell that both triggers and coordinates key events in the cell cycle.
Control system
G2 checkpointM checkpoint
G1 checkpoint
G1
S
G2M
~ similar to a clock
The cell cycle is regulated at certain checkpoints by both internal and external controls.
Checkpoint control system
• Checkpoints– cell cycle controlled by STOP & GO chemical
signals at critical points– signals indicate if key cellular
processes have been completed correctly
Checkpoint control system
• 3 major checkpoints:– G1/S
• can DNA synthesis begin?– G2/M
• has DNA synthesis been completed correctly?
• commitment to mitosis– spindle checkpoint
• are all chromosomes attached to spindle?
• can sister chromatids separate correctly?
Cdk / G1cyclin
Cdk / G2cyclin (MPF)
G2
S
G1
CM
G2 / M checkpoint
G1 / S checkpoint
APC
ActiveInactive
ActiveInactive
InactiveActive
mitosis
cytokinesis
MPF = Mitosis Promoting FactorAPC = Anaphase Promoting Complex
• Replication completed• DNA integrity
Chromosomes attached at metaphase plate
Spindle checkpoint
• Growth factors• Nutritional state of cell• Size of cell
G1/S checkpoint
• G1/S checkpoint is most critical– primary decision point
• “restriction point”– if cell receives “GO” signal, it divides
• internal signals: cell growth (size), cell nutrition • external signals: “growth factors”
– if cell does not receive signal, it exits cycle & switches to G0 phase
• non-dividing, working state
G0 phase
MMitosis
G1Gap 1
G0Resting
G2Gap 2
SSynthesis
• G0 phase– non-dividing, differentiated state– most human cells in G0 phase
liver cells in G0, but can be “called
back” to cell cycle by external cues
nerve & muscle cells highly specialized; arrested
in G0 & can never divide
Cell Cycle Checkpoints• If cell size inadequate
– G1 or G2 arrest• If nutrient supply inadequate
– G1 arrest • If an essential external stimulus is lacking
– G1 arrest (at R)• If the DNA is not replicated
– S arrest• If DNA damage is detected
– G1 or G2 arrest• If the spindle formation is improper,
chromosome misalignment– M-phase arrest
R
“Go-ahead” signals• Protein signals that promote cell growth &
division– internal signals
• “promoting factors”– external signals
• “growth factors”
• Primary mechanism of control– phosphorylation
• kinase enzymes• either activates or inactivates cell signals
Cell cycle signals
• Cell cycle controls– cyclins
• regulatory proteins• levels cycle in the cell
– Cdk’s• cyclin-dependent kinases• phosphorylates cellular
proteins– activates or inactivates proteins
– Cdk-cyclin complex• triggers passage through
different stages of cell cycle
activated Cdk
inactivated Cdk
Types of Cyclins and Cdks
• There are many types of cyclins, but the 4 main ones are:– Cyclin D (G1 cyclin)– Cyclin E (S-phase cyclin)– Cyclin A (S-phase and mitotic cyclin)– Cyclin B (mitotic cyclin)
• These are the 3 main cdks– Cdk4 (G1 Cdk)– Cdk2 (S-phase Cdk)– Cdk1 (mitotic Cdk)
• The complex of Cdk1 and cyclin B is called mitosis promoting factor (MPF) a.k.a maturation promoting factor
Rise and fall of cyclinsCy
clin
Con
cent
ratio
n
Mitosis
Cdks and cyclinsCyclin-dependent kinases (Cdks) are enzymes that are present in the cell cytoplasm at all times.
However, they are inactive unless they are bound by a specific partner-protein called a cyclin to form a Cdk-cyclin complex
The amount of cyclins in the cell changes – because they get degraded
A Cdk-cyclin complex will push the cell cycle forward.
Figure 19-35 Phosphorylation and Dephosphorylation in the Activation of a Cdk-Cyclin Complex
MPF: M-phase Promoting Factor
• MPF is composed of two key subunits: Cdc2 and Cyclin B. – Cdc2 is the protein that encoded by genes
which are required for passage through START as well as for entry into mitosis.
– Cyclin B is a regulatory subunit required for catalytic activity of the Cdc2 protein kinase.
What does MPF do?The complex of Cdk1 and cyclin B is called mitosis promoting factor (MPF)
MPF activity is dependent upon Cyclin B
• The cyclins were identified as proteins that accumulate throughout interphase and are rapidly degraded toward the end of mitosis.
• It is suggested that they might function to induce mitosis, with their periodic accumulation and destruction controlling entry and exit from M phase.
MPF activity is dependent upon Cyclin B
• Accumulation and degradation of cyclins
Figure 19-34 Fluctuating Levels of Mitotic Cyclin and MPF During the Cell Cycle
MPF regulation
• Cdc2 forms complexes with cyclin B during S and G2. • Cdc2 is then phosphorylated on threonine-161, which
is required for Cdc2 activity, as well as on tyrosine-15 (and threonine-14 in vertebrate cells), which inhibits Cdc2 activity. Dephosphorylation of Thr14 and Tyr15 activates MPF at the G2 to M transition.
• MPF activity is then terminated toward the end of mitosis by proteolytic degradation of cyclin B.
MPF regulation• Demonstration of regulation of MPF
Figure 19-40 A General Model for Cell Cycle Regulation
Cyclins & Cdks• Interaction of Cdk’s & different cyclins triggers the stages of
the cell cycle
Leland H. Hartwellcheckpoints
Tim HuntCdks
Sir Paul Nursecyclins
1970s-’80s | 2001
• external signals is density-dependent inhibition, in which crowded cells stop dividing but lost of contact inhibition and outgrowth in cancer cells
Tumors
• Mass of abnormal cells– Benign tumor
• abnormal cells remain at original site as a lump – p53 has halted cell divisions
• most do not cause serious problems &can be removed by surgery
– Malignant tumors• cells leave original site
– lose attachment to nearby cells – carried by blood & lymph system to other tissues– start more tumors = metastasis
• impair functions of organs throughout body
Tumors
• Benign - A spontaneous growth of tissue which forms an abnormal mass is called a tumor. A tumor that is noninvasive and noncancerous is referred to as a benign tumor.
• Malignant - A tumor that invades neighboring cells and is cancerous is referred to as a malignant tumor.
• Matastasis – Cancer that has spread to other tissues.
Development of Cancer
• Cancer develops only after a cell experiences ~6 key mutations (“hits”)– unlimited growth
• turn on growth promoter genes– ignore checkpoints
• turn off tumor suppressor genes– escape apoptosis
• turn off suicide genes– immortality = unlimited divisions
• turn on chromosome maintenance genes– promotes blood vessel growth
• turn on blood vessel growth genes– overcome anchor & density dependence
• turn off touch censor gene
It’s like anout of controlcar!
MMitosis
G1Gap 1
G0Resting
G2Gap 2
SSynthesis
Cancer & Cell Growth
• Cancer is essentially a failure of cell division control – unrestrained, uncontrolled cell growth
• What control is lost?– checkpoint stops– gene p53 plays a key role in G1 checkpoint
• p53 protein halts cell division if it detects damaged DNA – stimulates repair enzymes to fix DNA – forces cell into G0 resting stage– keeps cell in G1 arrest – causes apoptosis of damaged cell
• ALL cancers have to shut down p53 activity
p53 is theCell CycleEnforcer
p53 discovered at Stony Brook by Dr. Arnold Levine
DNA damage is causedby heat, radiation, or chemicals.
p53 allows cellswith repairedDNA to divide.
Step 1
DNA damage iscaused by heat,radiation, or chemicals.
Step 1 Step 2
Damaged cells continue to divide.If other damage accumulates, thecell can turn cancerous.
Step 3p53 triggers the destruction of cells damaged beyond repair.
ABNORMAL p53
NORMAL p53
abnormalp53 protein
cancercell
Step 3The p53 protein fails to stopcell division and repair DNA.Cell divides without repair todamaged DNA.
Cell division stops, and p53 triggers enzymes to repair damaged region.
Step 2
DNA repair enzymep53protein p53
protein
p53 — master regulator gene
Growth Factors and Cancer
• Growth factors influence cell cycle– proto-oncogenes
• normal genes that become oncogenes (cancer-causing) when mutated
• stimulates cell growth• if switched on can cause cancer• example: RAS (activates cyclins)
– tumor-suppressor genes• inhibits cell division• if switched off can cause cancer• example: p53
What causes these “hits”?
• Mutations in cells can be triggered by UV radiation chemical exposure radiation exposure heat
cigarette smoke pollution age genetics
How we naturally fight cancer cells
• Tumor suppressor genes like p53– Can arrest the cell cycle– Can launch the apoptotic pathway, causing the
rogue cells to lyseA mutation in the p53 gene can lead to cancer
• Immune cells (WBCs) such as NK cells can attack and lyse tumor cells– Some immune cells can signal the rogue cells to
launch the apoptotic pathways
Traditional treatments for cancers• Treatments target rapidly dividing cells
– high-energy radiation • kills rapidly dividing cells
– chemotherapy• stop DNA replication• stop mitosis & cytokinesis• stop blood vessel growth
New “miracle drugs”
• Drugs targeting proteins (enzymes) found only in tumor cells– Gleevec
• treatment for adult leukemia (CML)& stomach cancer (GIST)
• 1st successful targeted drug
Any Questions??
Signal Transduction Pathways • What are they?
– Signal transduction refers to any process by which a cell converts one kind of signal or stimulus into another.
– A large number of proteins, enzymes and other molecules participate in a "signal cascade“
• What is the end result?– Either the activation or inhibition of a certain enzyme in
the cytoplasm– Either the expression or suppression of a particular gene
Just a few examples of Signal Transduction Pathways
• Cell Division signals• Apoptotic signals• Insulin pathways
Apoptotic Pathways
Insulin Signaling Pathway
The binding of insulin to its receptor on a cell starts a cascade of cellular events which finally leads to the uptake of glucose and the lowering of blood glucose levels.
“Go-ahead” signals• Protein signals that promote cell growth &
division– internal signals
• “promoting factors”– external signals
• “growth factors”
• Primary mechanism of control– phosphorylation
• kinase enzymes• either activates or inactivates cell signals