Cell Cycle Flashcards
G0
• Quiescent, intact proliferation capacity, non-cycling
G1 and Regulation
- Duration between completion of cell division and initiation of DNA replication where cells start building cell mass
- Cyclins: C,D 1-3, E 1-2, F, G
- CDK4/CDK6 binds with D
S and regulation
DNA replication
• Cyclin A binds with CDK2 and CDK1
G2 and regulation
Duration between completion of DNA replication and initiation of cell division
• Cyclins B 1-2 binds with CDK1
M-phase
Mitosis
(1) Kinase: CDK1, Cyclin A
- Triggers G2 to M transition
* Cyclin A is synthesized in S and destroyed starting at prometaphase
(2) Kinase: CDK1, Cyclin B
- Phosphorylation of the retinoblastoma susceptibility protein in G1
- Triggers passage of the restriction point and cyclin E synthesis in some cell types
(3) Kinase: CDK4/6 cyclin D
- Phosphorylation of the retinoblastoma susceptibility protein in G1
- Triggers passage of the restriction point and cyclin E synthesis in some cell types
(1) INK4 family (p16,15,18,19) (Cyclin D)
- Twisting of the Cdk upper lobe blocks cyclin binding or interferes with ATP hydrolysis
- Cooperates with the retinoblastoma susceptibility protein in growth regulation
- Cell-cycle arrest in senescence
- Altered in a high percentage of human cancers
(2) Cip/Kip families (p21-Cip1, p27-Kip1, p57-Kip2) (Cyclin A and B)
• A loop insinuates into the upper lobe of the Cdk and blocks ATP binding
• P21
(i) Induced by p53 tumor suppressor
(ii) Cell-cycle arrest after DNA damage
(iii) Binds PCNA and inhibits DNA synthesis
P27
-cell cycle arrest in response to growth suppressors like TGF-Beta and contact inhibition
What is the restriction point?
E-CDK2 complexes drive pRB hyperphosphorylation, this liberates E2F transcription factors from pRb control, enabling the E2Fs to trigger increased transcription of the cyclin E and E2F1
Cancer initiation
- Simple mutation in one or more genes that control key regulatory pathways of the cell
- Change in DNA sequence
- Irreversible
Cancer Promotion
- Selective functional enhancement of signal transduction pathways that were induced by initiator by continuous exposure
- Epigenetic event
- Over long period of time
- Reversible in early stages
Cancer progression
- Continuing change of the basically unstable karyotype
- Further changes in karyotype
- Irreversible changes
- Conversion of benign tumors into malignant neoplasms
Tumor suppressor genes
(6) Ex: p53, Rb, p14ARF, P16INK4A (gene mutation, deletion, CpG island methylation in promoter)
Radiation therapy
• Effective on cells which have
(i) Reproductive activity
(ii) Cells which no longer have dividing future ahead
(iii) Cells with morphology and function are least fixed
(iv) Direct deposit of energy to break DNA bonds
(v) Hydrolysis of water to produce powerful damaging free radicals
Chemotherapy
• Alkylating agents (i) Crosslinking of DNA chains • Antitumor antibiotics (i) Inhibition of topoisomerase II (ii) Intercalation • Antimetabolites (i) Inhibition of enzymes (ii) Introduction of false substances in DNA “poisons of the division spindle” • Enzymes (i) L-Asparaginase (ii) Enzymatic cleavage of asparagine • Unclassified chemotherapeutics (i) Crosslinking of DNA chains, destruction of enzymes
Apoptotic initiators
caspases 8,9,10
Apoptotic executioners
capases3,6,7
Anti-apoptotic
BCL-2 family
Pro-apoptotic
BH3 and BAX family
Autophagy
(a) Self destruction
(b) Due to starvation
(c) Membrane blebbing, accumulation of two-membrane autophagic vacuoles
(d) Caspase independent and increased lysosomal activity
• Mitotic catastrophe
(a) Aberrant mitosis
(b) Associated with deficiencies in cell cycle checkpoints, formation of giant cell, micronuclearization and multinucleation
(c) Defects in cell cycle checkpoints
(i) P53- G2 checkpoint
(ii) BUBR- spindle checkpoint
(iii) APC- spindle assembly
(d) Hyper amplification of centrosomes
(i) Usually in subsequent cell cycle
(e) Capspase-2 activation during metaphase
(i) Delayed apoptosis
