Transcript Cell Regulation 2

P53, Apoptosis, Cancer, More
Regulation
G1 checkpoint
• Controlled by G1
Cdk-cyclin
• G1 cyclin levels
also vary with the
cell cycle
• Many additional
levels of
phosphorylation,
dephosphorylation regulate.
Cyc D
cdk4
P
E2FP
PE2F
pRB
E2FP
PE2F
E2F E2F
E2F
E2F
Cyc E
cdk2
Growth Factor Signaling Through the Ras Pathway 
crossing of G1 checkpoint
Ras*, Raf*
MAPK
cascade
Activation of
nuclear TFs
Activation of
G1 Cdk cyclin
genes: G1  S
G2 Checkpoint Control by MPF
• Active MPF = Mitotic Cdk + mitotic cyclin
• Cdk is cyclin-dependant kinase
• MPF controls G2  M by phosphorylating and
activating proteins involving in:
– Chromosome condensation
– Nuclear envelope breakdown
– Spindle assembly
– It’s own self-destruction
G2
checkpoint
Sister chromatid separation from prometaphase to anaphase
Check
Check
APC
Separase
point
APC
Separase
point
Securin
Securin
Separase
Cohesin
Cohesin
Securin
prometaphase
metaphase
anaphase
Spindle Assembly Checkpoint Controls
Metaphase  Anaphase
•
MPF (+) anaphase promoting
complex, which destroys:
1.
2.
Securin, which allows separin
protease to cleave cohesin.
Mitotic cyclin, which causes loss of
MPF activity, leading to
chromosome decondensation and
envelope reformation.
(+)
Section 20.2: Control of Mitosis by Cyclins and MPF Activity
Maturation promoting factor (MPF) is a protein kinase
(requiring a mitotic cyclin) that stimulates mitosis,
and hence is also called mitosis promoting factor.
The increase and decrease in MPF activity during the
cell cycle in the early embryo reflects the cyclic synthesis
and degradation of mitotic cyclins.
The anaphase-promoting complex/cyclosome (APC/C) is a
ubiquitin ligase that recognizes the destruction box sequence
in mitotic cyclins, marking them for degradation in late anaphase
and thus terminating mitosis.
Deactivation of APC/C (by G1-cyclin/CDK) in G1 permits mitotic
(and S phase) cyclins to accumulate, allowing the cell cycle to
continue.
DEF: A gene which encodes a protein that regulates all
growth and is able to cause potential cancerous cells to
destroy themselves. The gene is an antioncogen.
F(x): Includes regulation of critical cellular function
involving the G1 and G2 cell-cycle check points in
response to DNA damage and apoptosis induced by
certain stimuli, such as DNA damaging agents and
hypoxia.
Additional F(x): The tumor suppressor gene functions
as the “guardian of the genome” plays a pivotal roe in
“sending” damaged DNA and in making critical
decisions of whether a cell should repair the damaged
DNA.
The tumor suppressor gene p53 is located
at chromosomes region 17p13 and is one
of the most frequently mutated gene in
human cancers.
APOPTOSIS
Programmed cell death
Orderly cellular self destruction
Process: as crucial for survival of multi-cellular
organisms as cell division
IMPORTANCE OF APOPTOSIS
• Important in normal physiology / development
– Development: Immune systems maturation,
Morphogenesis, Neural development
– Adult: Immune privilege, DNA Damage and wound repair.
• Excess apoptosis
– Neurodegenerative diseases
• Deficient apoptosis
– Cancer
– Autoimmunity
STAGES OF CLASSIC APOPTOSIS
Healthy cell
DEATH SIGNAL (extrinsic or intrinsic)
Commitment to die (reversible)
EXECUTION (irreversible)
Dead cell (condensed, crosslinked)
ENGULFMENT (macrophages, neighboring cells)
DEGRADATION
APOPTOSIS: Role in Disease
TOO MUCH: Tissue atrophy
Neurodegeneration
Thin skin
etc
TOO LITTLE: Hyperplasia
Cancer
Athersclerosis
etc
APOPTOSIS: Role in Disease: Cancer
Apoptosis eliminates damaged cells
(damage => mutations => cancer
Tumor suppressor p53 controls senescence
and apoptosis responses to damage
Most cancer cells are defective in apoptotic response
(damaged, mutant cells survive)
High levels of anti-apoptotic proteins
or
Low levels of pro-apoptotic proteins
===> CANCER
OPTIMAL FUNCTION (HEALTH)
APOPTOSIS
AGING
APOPTOSIS
Neurodegeneration, cancer, …..
P53 & Apoptosis
p53 first arrests cell growth between G1  S
This allows for DNA repair during delay
If the damage is too extensive then p53
induces gene activation leading to
apoptosis (programmed cell death)
Cancer: Benign
• Benign: localized and of
small size
• Cells that closely
resemble, and may
function, like normal cells
• Become problems due to
sheer bulk or due to
secretions (e.g.
hormones)
Cancer : Malignant
Malignant tumors: high rate of division, properties may vary
compared
to cells of origin. Most malignant cells become
metastatic
Invade surrounding tissue and establishment of secondary areas of
growth: Metastasis
Metastasis
Carcinoma: derived from endoderm or ectoderm
Events in metastasis.
Cancer has a lot to do with cell signaling for growth
Pathways leading to cancer