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CELL CYCLE.pptx
1. CELL CYCLE
&
BIOCHEMISTRY OF CANCER
Dr MANJU JHA
MBBS, MD
Department of Biochemistry
RUHS College of Medical Sciences, Jaipur
2. cell cycle:
It is a series of
events that takes
place in a
proliferating cell
(normal and
malignant ) leading
to its division and
duplication
3. G0: RESTING
When the cell get a signal to
reproduce, they move into the
G₁ Phase.
INTERPHASE:
G0, G1, S, G2
4. G₁ PHASE (Pre-synthetic phase):
The cell starts to produce
proteins and enzymes necessary
for DNA synthesis.
During this phase, RNA synthesis
occurs.
5. S-PHASE (synthetic phase)
DNA synthesis
Cellular DNA is duplicated in
preparation in preparation for
cellular division.
A weak link, and large number
of anticancer agent act here.
6. G₂ Phase (pre-mitotic phase):
The cell checks the DNA
Gets ready to start splitting into
2 cells
Here both protein, RNA, and the
precursors to the mitotic
spindle apparatus are produced.
This phase is very short…..
7. MITOTIC PHASE:
In this phase, which last only 30-
60min, the cell actually split into
2 new cells.
Mitotic phase:
PROPHASE
METAPHASE
ANAPHASE
TELOPHASE
10. Role of cyclins, cyclin-dependent kinases
(CDKs) and CDK inhibitors (CDKIs) in
regulating the cell cycle.
Shaded arrows represent the phases of the cell
cycle during which specific cyclin-CDK complexes
are active.
As illustrated, cyclin D-CDK4, cyclin D-CDK6,
and cyclin E-CDK2 regulate the G1-to-S transition
by phosphorylating the Rb protein (pRb).
Cyclin A-CDK2 and cyclin A-CDK1 are active in
the S phase.
Cyclin B-CDK1 is essential for the G2-to-M
transition.
Two families of CDK inhibitors can block activity
of CDKs and progression through the cell cycle.
The so-called INK4 inhibitors, composed of p15,
p16, p18, and p19, act on cyclin D-CDK4 and
cyclin D-CDK6. The other family of three
inhibitors, p21, p27, and p57, can inhibit all CDKs.
11. Cell cycle components and inhibitors that
are frequently mutated in cancer
CIP/KIP family are CDK Inhibitors
INK4 ia a family of CDK Inhibitors (CKIs)
p16INK4a
p15INK4b
p18INK4c
p19INK4d
INhibitors of Kinase
12. Checkpoints control transitions between phases of
cell cycle. This process is regulated by cyclins,
cyclin-dependent kinases (CDKs), and tumor
suppressors.
M phase (shortest phase of cell cycle) includes mitosis (prophase, prometaphase, metaphase, anaphase,
telophase) and cytokinesis (cytoplasm splits in two).
G1 and G0 are of variable duration
13. Cyclin-dependent kinases (CDKs):
Key regulators of cell cycle
Constitutively expressed but inactive when not
bound to cyclin
Cyclins:
Regulatory proteins that control cell cycle events;
phase specific; activate CDKs. They increases CDK
activity & CDK-Inhibitor proteins decreases it.
14. Cyclins:
Synthesized during one phase of cell cycle and
degraded in other phase.
In order to enter in the new phase in the cell cycle, a
cell must satisfy a corresponding checkpoint, which
monitors whether the cell has satisfactorily
completed the preceding phase.
15. Cyclin-CDK complexes:
Phosphorylate other proteins to coordinate cell
cycle progression,
Must be activated and inactivated at appropriate
times for cell cycle to progress
16. When growth factores (via TK) stimulates
quiescent cells (G0) to enter into G1 phase-cyclins
activated CDK phosphorylate the Rb protein.
After phosphorylation Rb no longer binds to E2F
transcription factor.
E2F alter transcription in cells to fit need of the
cell cycle ie. Replication.
Free E2F alter the expression of proteins to favor
progress in the cell cycle.
17.
18. p53 -> p21 induction -> CDK inhibition->
Rb hypophosphorylation (activation) -> G1-S
progression inhibition.
Mutations in tumor suppressor genes can result
in unrestrained cell division (eg, Li-Fraumeni
syndrome).
Growth factors (eg, insulin, PDGF, EPO, EGF) bind
tyrosine kinase receptors to transition the cell from
G1 to S phase.
19. Permanent Remain in G0,
regenerate from stem
cells
Neurons, skeletal and cardiac
muscle, RBCs
Stable
(quiescent)
Enter G1 from G0 when
stimulated
Hepatocytes, lymphocytes,
PCT, periosteal cells
Labile Never go to G0,
divide rapidly with a
short G1
Most affected by
chemotherapy. Bone marrow,
gut epithelium, skin, hair
follicles, germ cells.
22. Tumor: Fatality 2nd to CVD
Benign or Malignant
Worldwide, approximately 25% deaths occur due
to Cancer.
Most susceptible organ to cancer are: Lung,
Large intestine, & breast.
23. Properties of malignant tissue:
• Rapid growth
• Loss of contact inhibition
• Insensitive to anti-growth factors
• Invasion to various tissues and organs
• Stimulation of angiogenesis
• Immortal due to inhibition of apoptosis
• De-differentiation
24. • Cell cycle time: Normal-18-24 hours (Increased 2-5 times)
• Cell proliferation (proliferation coefficient)-dividing/resting cells
• Morphology: irregular nucleus, prominent nucleoli, scarce cytoplasm, multilayered instead of
monolayer
• Loss of contact inhibition: ex-deep cut
• Tissue adherence lost: vinculin-deactivated by phosphorylation by tyrosine kinase, decreased
adherence facilitates metastasis
• Role of sialylation: cell surface is highly negative charged due to higher NANA, which prevents
adhesion of cells. Sialidase decreases in malignancy…
• Inactivation of apoptosis
• Metastasis
• Angiogenesis
• Metabolic alteration: Cancer cell metabolizing sugar mainly by anaerobic glycolysis by eliminating the
role of enzymes of TCA & ETC. Certain proteins & enzymes also altered.
26. DEFINITIONS-
CANCER: A group of disease involving abnormal cell
growth with the potential to invade or spread to other
part of the body.
CHEMOTHERAPY: The use of chemicals or drugs to
treat cancer.
CYTOTOXIC DRUG: Drugs that lysis both normal and
cancer cells
Editor's Notes
A particular cyclin specifically bind to and thereby activates its corresponding CDK to phosphorylate its target proteins, thus activating these proteins to carry out the process in that particular cycle.