Transcript Cell Cycle III

Growth Factors Induce Cell Proliferation
Growth Factors
act Prior to
the Restriction Point
Modified from The Biology of Cancer (© Garland Science 2007)
Let’s think about the Difference Between Growth and Cell Division
Growth with
No Cell Division
Cell Division
No Growth
Cell Division + Growth =
Proliferation!
Growth with
No Cell Division:
A Differentiated Neuron
Cell Division with No Growth: Early Development
OOCYTE GROWS WITHOUT DIVIDING
(MONTHS)
FERTILIZATION
FERTILIZED EGG DIVIDES WITHOUT GROWING
(HOURS)
1 mm
sperm
tadpole feeds, grows
and bcecomes an adult frog
A Typical Solid Tumor…Needs to Grow
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!
Budding Yeast Saccharomyces cerevisiae
Cdc Mutants Affect the Cell Cycle, Not Growth
Permissive (low) temperature
Restrictive (high) temperature
Mammalian Cells Growing in Cell Culture
Amino
Acids
Arginine
Cystine
Glutamine
Histidine
Isoleucine
Leucine
Lysine
Methionine
Phenylalanine
Threonine
Tryptophan
Tyrosine
Valine
Vitamins
Salts
Miscellaneous
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)
L6
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 Induce Cell Proliferation
Growth + Cell Cycle Progression: But How?
Growth Factors
act Prior to
the Restriction Point
Modified from The Biology of Cancer (© Garland Science 2007)
Growth Factors Induce Gene Expression
Growth Factors Induce Oncogene Expression
As 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 cyclins
2 A-type cyclins
3 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 TRANSLOCATION
T(11;11)(Q13;P15) THAT INVOLVES CCND1 AND THE PARATHYROID HORMONE (PTH) ENHANCER (PRAD1 ONCOGENE).
Translocations Cause One Gene
to be Controlled by Another
Cell Cycle Checkpoints
The Guardian Mechanisms of
the Genome
THEY ARE DISRUPTED
IN CANCER!
Figure 8.4 The Biology of Cancer (© Garland Science 2007)
Entering Mitosis Before the Completion of S phase is
Bad for Chromosomes and Therefore Bad for Cells
Caffeine Abrogates the Replication Checkpoint
The point: the combination of cellular stress and an inactive
Checkpoint is very detrimental to cells.
Molecular Biology of the Cell © 1994 by Bruce Alberts et al
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
Cytoplasm
Nucleus
Remember Kinetochore/Microtubule Attachments
During Metaphase?
Microtubule
Kinetochore
Remember the Metaphase to Anaphase Transition?
Lara-Gonzalez et al. Current Biology Volume 22, Issue 22 2012 R966 - R980
Mitotic Defects Leading to Aneuploidy
Weaver BA, Cleveland DW. Does aneuploidy cause cancer? Curr Opin Cell Biol. 2006 Dec;18(6):658-667.
The Spindle Assembly Checkpoint Prevents Anaphase Errors
Very robust:
e.g. A single unattached
kinteochore will activate
the SAC
Lara-Gonzalez et al. Current Biology Volume 22, Issue 22 2012 R966 - R980
Spindle Assembly Checkpoint Genes that are Mutated
and/or Misregulated in Human Cancers
Weaver BA, Cleveland DW. Does aneuploidy cause cancer? Curr Opin Cell Biol. 2006 Dec;18(6):658-667.