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1'Cell cycle regulation is the central control system of cell

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Title: 1'Cell cycle regulation is the central control system of cell


1
WHY WE STUDY CELL CYCLE CONTROL?
1. Cell cycle regulation is the central control
system of cell life. 2. Study of cell cycle
regulation will expose many important
biological and biochemical events linked to
cell proliferation, differentiation, and
apoptosis. 3. Cell cycle study will expose the
mechanisms leading to cancer, which has
significant implication on cancer diagnosis and
cancer treatment. As a evidence of the
importance of cell cycle study, 2001 Nobel Prize
for Medicine or Physiology was awarded to three
scientists for their pioneering work involving
discovery of key regulators of the cell cycle.
C1
2
In the G1 the cell grows. When it reaches a
certain size, it enters S phase where the
chromosomes are duplicated. During the G2 the
cell prepares itself for division. During M phase
the chromosomes are separated and segregated to
the daughter cells, which thereby get exactly
the same chromosome set up. The cells are then
back in G1 and the cell cycle is completed. The
daughter cells can either start the cycle again
by entering G1, or it can become quiescent by
entering G0.
C2
3
A complex of cyclin/cdk has kinase activity

Target proteins
active cyclin/cdk complex
cyclin cdk
Cdk is a protein kinase that activates numerous
cell proteins by phosphorylating them. Cyclin is
a regulatory protein required to activate cdk.
In other words, cdk does not function unless
cyclin is bound to it.
Major cdks and their regulatory subunits involved
in cell cycle control.
Cdc 2(cdk1) cyclin B cdk2 cyclin
A cyclin E cdk4 cyclin D1 cyclin
D2 cyclin D3 cdk 6 cyclin
D1 cyclin D2 cyclin D3
C3
4
Wee1
P
cdc2
Cdc25c
P
Chk
Cdc2/cyclinB
Cdk4/cyclin D Cdk6/cyclin D
Cdc25c/14-3-3
P
M
G2
G1
S
Cdk2/cyclin A
Cdk2/cyclin E
Cdk/cyclin D
Dephosporylated pRb Phosphorylated pRb
G1 progress and DNA synthesis
Cdc2/cyclin B promotes G2-M transition and M
progress cdk/cylin D, cylin E, and cyclin A
complexes promotes G1 progress, G1-S
transition,and S progress, respectively.
C4
5
Cyclin-dependent Kinase Inhibitors
Type Name
Function
P15INK4B p16INK4A p18INK4C p19INK4D
Ink inhibitors only bind to and inhibits cdk4
and cdk6
INK
P21WAF1/CIP1 p27KIP1 p57KIP2
Kip/Cip inhibitors can bind to and inhibit both
cyclin D-cdk4/6 kinases as well as
cyclin-E/A-cdk2.
KIP/CIP
Cdk4/cyclin D Cdk6/cyclin D
M
G2
G1
S
Cdk2/cyclin A
Cdk2/cyclin E
C5
p27
6
Cyclin D-cdk4/6
p
p
p
pRb
p
p
pRb
p
p
E2F
E2F
Transcription repressed Transcription
activated
G1
S
E2F E2F-1, E2F-2, E2F-3, E2F-4, E2F-5
E2F-4
Fig. 5. The pRb-E2F pathway. In G1, pRb binds to
E2F and represses transcription of
E2F-responsive genes, leading to a cell-cycle
block. Cyclin D-cdk4/6 can mediate
phosphorylation and prevent the formation of
pRb-E2F complex. The liberation of free E2F
leads to the activation of E2F-responsive genes
and cells entry into S phase.
C6
7
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8
C8
GROWTH FACTORS OF MAMMALIAN CELLS
Growth Range of Factor
Specificity Effects
Epidermal growth Broad Stimulates cell
proliferation in many tissues factor
(EGF) play a key role in regulating embryonic
development Erythropoietin
Narrow Required for proliferation of red blood
cell precursors and their maturation into
erythrocytes Granulocyte-macrophage
Narrow Stimulates proliferation and
differentiation of colony-stimulating
factor multilineage hematopoietic progenitor
cells (GM-CSF) Fibroblast growth Broad Initiat
es the proliferation of many cell types factor
(FGF) inhibits maturation of many types of
stem cells Platelet-derivel growth Broad
Promotes the proliferation of many
connective factor (PDGF) tissues and some
neuroglial cells. Transforming growth
Broad Inhibits growth in most type of cells
factor-? (TGF-?)
9
Effect of TGF? on cell cycle
Effect of TGF? on cell growth
100 80 60 40 20 0
TGF? - TGF?
Phase
MTT ASSAY ()
G1 47.3 82 S 45.6
12.8 G2/M 7.1 5.2
TGF? - TGF?
Effect of TGF? on cdk/cyclin
Effect of TGF? on p27
cdk4
p27
- TGF?
cyclin D3
- TGF?
Effect of TGF? on pRb/E2F
complex
Effect of TGF? on pRb phosphorylation
ppRb pRb
pRb/E2F-4 complex
- TGF?
- TGF?
Mechanism by which TGF? inhibits cell growth
TGF? arrests cells in G1 phase TGF?
downregulates cdks and cyclins TGF? upregulates
p27 TGF? dephosphorylates pRb TGF? affects
formation of pRb-E2F complexes
C9
10
Cell Cycle Regulatory Molecules/genes and Cancer
Gene/Protein Cancer
Gene Mutation
p53
More than 50 cancers
Rb
More than 40 of cancers including
retinoblastoma, Osteosarcomas, Small cell lung
carcinomas, Breast cancer.
p16
Sporadic cancer Melanoma
p21
Breast carcinoma Malignant melanoma Lymphoma
Abnormal Expression
p27
Colorectal cancer breast cancer, Prostate cancer
Esophageal cancer Gastric cancer Ovarian
cancer Lung cancer Malignant melanomas Pancreatic
carcinomas
Cyclin/cdk
Gliomas Sarcomas
C10
11
1. The eukaryotic cell cycle is divided
into four distinct phases G1, S, G2, and M,
which is regulated by two types of proteins,
cyclins and cyclin-dependent protein
kinases. 2. In mammalian cells, G2-M
transition is directly controlled by active
cdc2/cyclin B complex, whereas G1 progress and
G1/S transition are regulated by cdk4/6-cyclin D
and cdk2-cyclin E/A, respectively. The targets of
cdc2 are the proteins affecting membrane
structure and chromosome condensation,
whereas cyclin D-cdk4/6 modifies pRb. 3.
The activity of G1 cyclin-cdk complexes is
negatively regulated by cdk inhibitors (ink and
cip/kip families). 4. pRb-E2F complex is a
repressor of E2F-dependent trans- cription. p53
inhibits cells in G1 in response to DNA damage.
5. G1 phase responds to extracelluar
signals such as growth factors. TGFbeta arrests
cells in G1 through inhibiting the expression
of cdk/cyclin and upregulating p27. 6.
Failures of cell cycle regulation can lead to
uncontrolled cell growth and induce cancer.
SUMMARY
C11
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