growth factors act prior to the restriction point growth factors induce cell proliferation modified...
TRANSCRIPT
Growth Factors act Prior to
the Restriction Point
Growth Factors Induce Cell Proliferation
Modified from The Biology of Cancer (© Garland Science 2007)
Let’s think about the Difference Between Growth and Cell Division
Cell DivisionNo Growth
Cell Division + Growth =Proliferation!
Growth with
No Cell Division
Growth withNo Cell Division:
A Differentiated Neuron
Cell Division with No Growth: Early Development
1 mm
spermtadpole feeds, grows
and bcecomes an adult frog
OOCYTE GROWS WITHOUT DIVIDING(MONTHS) FERTILIZATION
FERTILIZED EGG DIVIDES WITHOUT GROWING(HOURS)
The size of a tumor first detectable by X-ray: 108 cells
The size of a tumor first palpable: 109 cells
The size of tumor at death of patient: 1012 cells
Unregulated Proliferation: Cancer!
A Typical Solid Tumor…Needs to Grow
Budding Yeast Saccharomyces cerevisiae
Permissive (low) temperature Restrictive (high) temperature
Cdc Mutants Affect the Cell Cycle, Not Growth
Mammalian Cells Growing in Cell Culture
Amino Acids Vitamins Salts Miscellaneous
Arginine
Cystine
Glutamine
Histidine
Isoleucine
Leucine
Lysine
Methionine
Phenylalanine
Threonine
Tryptophan
Tyrosine
Valine
Biotin
Choline
Folate
Nicotinamide
Pantothenate
Pyridoxal
Thiamine
Riboflavin
NaCl
KCl
NaH2PO4
NaHCO3
CaCl2
MgCl2
Glucose
Penicillin
Streptomycin
Phenol red
Whole serum
Specific growth factors
1961Hayflick and Moorhead Showed that human fibroblasts die after a finite number of divisions in culture.This is called “The Hayflick Limit”
Some Commonly Used Cell Lines
Cell Line* Cell Type and Origin
3T 3 fibroblast (mouse)
BHK 21 fibroblast (Syrian hamster)
MDCK epithelial cell (dog)
HeLa epithelial cell (human)
PtK 1 epithelial cell (rat kangaroo)
L 6 myoblast (rat)
PC 12 chromaffin cell (rat)
SP 2 plasma cell (mouse)
*Many of these cell lines were derived from tumors. All of them are capable of indefinite replication in culture and express at least some of the differentiated properties of their cell of origin. BHK 21 cells, HeLa cells, and SP 2 cells are capable of growth in suspension; the other cell lines require a solid culture substratum in order to multiply.
Growth Factors act Prior to
the Restriction Point
Growth Factors Induce Cell ProliferationGrowth + Cell Cycle Progression: But How?
Modified from The Biology of Cancer (© Garland Science 2007)
Growth Factors Induce Gene Expression
Growth Factors Induce Oncogene ExpressionAs Early Response Genes
Growth Factors Induce Cyclin D Expression
They also act by inhibiting CKIs
We actually have:
3 D-type cyclins 2 E-type cyclins2 A-type cyclins3 B-type cyclins
And the D-type cyclins respond to different cues
Growth Factors Get the Cell Cycle Going
Growth Factors Induce Cyclin D Expression
ONCOGENES!!!!
So, is Cyclin D an oncogene?
YES! Cyclin D is also an Oncogene
Disease: INVOLVED IN B-LYMPHOCYTIC MALIGNANCY (PARTICULARLY MANTLE-CELL LYMPHOMA)BY A CHROMOSOMAL TRANSLOCATION T(11;14)(Q13;Q32) THAT INVOLVES CCND1 AND IMMUNOGLOBULIN GENE REGIONS (BCL1 ONCOGENE).
Disease: INVOLVED IN A SUBSET OF PARATHYROID ADENOMAS BY A CHROMOSOMAL TRANSLOCATIONT(11;11)(Q13;P15) THAT INVOLVES CCND1 AND THE PARATHYROID HORMONE (PTH) ENHANCER (PRAD1 ONCOGENE).
Translocations Cause One Geneto be Controlled by Another
Figure 8.4 The Biology of Cancer (© Garland Science 2007)
Cell Cycle CheckpointsThe Guardian Mechanisms of
the Genome
THEY ARE DISRUPTED IN CANCER!
Entering Mitosis Before the Completion of S phase isBad for Chromosomes and Therefore Bad for Cells
Caffeine Abrogates the Replication Checkpoint
Molecular Biology of the Cell © 1994 by Bruce Alberts et al
The point: the combination of cellular stress and an inactive Checkpoint is very detrimental to cells.
How do Cell Cycle Checkpoints Work?
Zhou and Elledge Nature 408, 433 - 439 (2000)
Remember Inhibitory CDK Phosphorylation?
is a kinase is a phosphatase
G2 Arrest Induced by DNA Damage
Signal
Sensor
Transducer
Effector
Nucleus
Cytoplasm
Remember Kinetochore/Microtubule Attachments During Metaphase?
Kinetochore
Microtubule
Remember the Metaphase to Anaphase Transition?
Lara-Gonzalez et al. Current Biology Volume 22, Issue 22 2012 R966 - R980
Weaver BA, Cleveland DW. Does aneuploidy cause cancer? Curr Opin Cell Biol. 2006 Dec;18(6):658-667.
Mitotic Defects Leading to Aneuploidy
The Spindle Assembly Checkpoint Prevents Anaphase Errors
Lara-Gonzalez et al. Current Biology Volume 22, Issue 22 2012 R966 - R980
Very robust:e.g. A single unattachedkinteochore will activate the SAC
Weaver BA, Cleveland DW. Does aneuploidy cause cancer? Curr Opin Cell Biol. 2006 Dec;18(6):658-667.
Spindle Assembly Checkpoint Genes that are Mutated and/or Misregulated in Human Cancers