cell cycle, apoptosis and cancer Flashcards
S phase of cell cycle
synthesis, chromosome duplication
M phase of cell cycle
Mitosis
- Chromosome
Duplication/Segregation
- Cytokinesis- Cell Division
Go Phase
Poor nutrient/environmental condition
cells withdraw from the cell cycle
Also occurs following terminal differentiation in certain tissue types (e.g. brain
neurons, cardiac muscle, RBCs)
interphase
(G1) = Gap 1 phase- RNA and protein synthesis needed for DNA replication
(S) Phase DNA synthesis
(G2) Gap 2 phase- DNA stability is checked
Restriction point cell cycle
between G1 and S phase
-if growth factors are limited
what are checkpoints in cell cycle?
1) restriction point
2) G1 checkpoint
3) metaphase checkpoint
4) G2 checkpoint
G1 checkpoint
- Timing is similar to restriction point
- Occurs in response to DNA damage
G2 checkpoint
-Verify complete genomic duplication
metaphase checkpoint
-Ensures chromosomes attached to mitotic spindle
how does RB act as a tumor suppressor?
sequester E2F
What does entry from S phase to G1 require?
E2F to be active
what phosphorylates RB to make it inactive and activated E2F?
CDK2
what do cyclins require to be active?
- cyclins
- CAK (t loop in cave site)
what expression rises and falls throughout the cell cycle?
Cyclin expression
-causes kinase activity to rise and fall
CDK4 and CDK6
helps the passage of cells through the restriction point in late G1 phase
Wee1 Kinase
inhibits Cdk activity by phosphorylating the roof site
Cdc25
dephosphorylates roof site to increase CDK activity
CKI (p27)
bind to Cdk and cyclin
-inhibits (G1 to S transition)
Metaphase to anaphase requires which key regulator?
APC/C (cyclosome)
-member of ubiquitin ligase family of enzymes
what does APC/C do?
-activated by Cdc20
addition of polyubiqutin to S and M cyclin complexes
-cyclins targeted for destruction by proteasome
-inactivates CdKs
p53
- activated by phosphorylation
-leads to increased transcription of CKI (P21)
p21= cell cycle arrest
what keeps p53 inactive?
E3 ubiquitin ligase (MDM2)
p21
- is a CKI
- primarily associated with inhibiting CDK2
- major target of P53
extrinsic (death receptor) pathway
- Fas ligand activates FADD
- Procaspase 8 to caspase 8
- activates caspase 3,6,7
- apoptosis
intrinsic (mitochondrial pathway)
- Caspase 8 active
- release of cyt C from Mito
- APAF-1 forms apoptosome
- activates Caspase 9
- activates caspase 3,6,7
- apoptosis
what are the initiators caspases
Caspase-8 and Caspase-9
what are the executioner caspases
caspase 3
what stimulates the intrinsic apoptotic pathway?
- p53
- BAX
- BAK
what inhibits the intrinsic apoptotic pathway
BCL2
BCL XL
how does proto oncogene become an oncogene
gain of function mutation
Her2 Receptor to oncogene
becomes oncogene after Val replaced with Gln
- RTK activity always active
- becomes NEU
- breast cancer
- Gain of Function
EGF receptor to oncogene
deletion changes to EGFRvIII
RTK activity always active
-Glioblastoma
ABL and BCR gene to oncogene
translocation creates BCR-ABL gene
- acts as TF
- Chronic myelogenous leukemia (CML)
hereditary form of retinoblastoma
- mutation/deletion in one copy of RB1 (heterozygous)
- second hit required for cancer
- loss of heterozygosity
sporadic form of retinoblastoma
- non hereditary
- cancerous cell have both copies of RB1 mutated
- rare
- requires 2 indp. mutations
loss of function mutations in tumor suppressor genes
- p53
- RB
- APC
- DCC
- BRCA1/BRCA2
- NF-1
Metastasis Suppressors
Cell adhesion proteins
- Prevent tumor cells from dispersing
- Block loss of contact inhibition
- Inhibit tumor metastasis
Hallmarks of cancer cells
1) self sufficiency in growth signals
2) evading growth suppressors
3) activating invasion and metastasis
4) enabling replicative immortality
5) inducible angiogenesis
6) resisting cell death
ex of a viral oncogene
HPV
Viral oncogenes
proto oncogene infected by virus- viral genome integrates
- virus replicates
- protooncogene mutated to oncogene
- can infect other cells
alkylating agents
- block DNA replication
- all phases of cell cycle
antimetabolites
- inhibit enzymes involved in DNA synthesis
- S phase
Topoisomerase II inhibitors
- S phase G2 phase M phase
mitotic inhibitors
- arrest cells in mitosis during metaphase
- M phase
cytotoxic antibiotics
- intercalate between bases in DNA to inhibit DNA synthesis
- S and G2 phase
topoisomerase I inhibitor
- S phase
Herceptin
-targets HER2 receptor or NEU
Gleevec
- works with BCR/ABL enzyme and prevents phosphorylation of target protein
- used in CML
