Cancer II Flashcards
what are tumor suppressor genes and how do they do their duty?
- TSGs generally encode proteins that inhibit cell proliferation
- they encode proteins that restrict cell growth and proliferation AND/OR proteins that maintain integrity of the genome
what are some examples of proteins that normally restrict cell growth and proliferation?
proteins that inhibit progression through G1/S in cell cycle (eg. Rb, CKI)
receptors or components of a signaling pathway that inhibit cell proliferation
proteins that promote apoptosis (caspases)
what are some examples of proteins that maintain integrity of the genome
- check point control proteins (ATM, ATR - detect DNA damage - stops cell cycle)
- ATAXIA TELANGIECTASIA **
- DNA repair enzymes or pathways
What are some stats on Retinoblastoma?
- its a TSG; prevents over-proliferation of cells by inhibiting cell division
- inherited eye cancer in children
- rare childhood tumor: 1/20,000
- occurs before age 2
- 95% of cases diagnosed before age 5
- loss of BOTH Rb genes leads to cell and tumor proliferation in retina
How many forms of retinoblastoma are there and what are they? how would you detect them?
there are two forms: hereditary and sporadic
- 40% is familial in which bot eyes are affected (tumors)
- 60% of retinoblastoma is sporadic (no family history) - single tumor, one eye
hereditary form Rb
loss of function or deletion of one copy of Rb in every cell- because defect is INHERITED
these cells are predisposed to be cancerous, but still have one good Rb gene copy
somatic event occurs - eliminates the one good copy and tumor forms
this is called LOH - loss of heterozygosity
Sporadic form Rb
- non-hereditary – start off with all normal cells
- cancerous cells have both copies of Rb mutated
- *Two- hit hypothesis – first Rb gene obtains mutation then need second mutation Rb
- Rb protein is a regulator of cell cycle
how does Rb protein work?
- remember that E2F binds to PROMOTORS of G1/S cyclin and S cyclin genes, which drives cell to divide
- E2F is inhibited by interaction with Rb protein (Rb inhibits cell division this way.)
- Rb protein can be inactivated by phosphorylation
- loss of Rb means no control over cell proliferation
explain how Rb pathway includes proto-oncogenes and tumor suppressor genes
- Cdk or cyclin overproduced = oncogene
- overproduction of cyclin or Cdk genes could overcome amount of CKI’s; phosphorylate Rb so cannot stop E2F, which leads to uncontrolled growth (cancer)
- CKI or Rb = TSG
- CKI or Rb could be lost, leading to cancer. No CKI = no control of Cdk-cyclins; no Rb = no suppression of E2F; both mean entry into cell division at cancerous rates
what is p53?
its a huge tumor suppressor gene. its involved in (1) cell cycle arrest; (2) DNA repair; (3) apoptosis; (4) block of angiogenesis;
over 50% of cancers have mutation in p53
what happens if you lose p53?
you lose several functions
- loss of checkpoint control in cell cycle
- loss of cell cylce arrest in response to DNA damage
- loss of DNA repair activity
- loss of apoptosis in response to DNA damage
what else does p53 do?
(1) stimulates transcription of gene encoding CKI called p21 (p21 binds to G1/S-Cdk and S-Cdk, stopping cell cycle)
(2) p53 also activates expression of pro-apoptotic proteins BH123 (proteins that aggregate on mito surface, inducing cytochrome c release) and BH-3 only (protein that blocks Bcl2 activity, inducing apoptosis)
what are a few things that activate p53? what does it lead to?
hyperproliferative signals, DNA damage, telomere shortening, hypoxia
cell cycle arrest, senescence, apoptosis
what is one virus that causes cancer?
papilloma virus - causes warts and cervical cancer
how?
typically the viral DNA exists as extrachromosomal material (plasmid-like); but if the viral DNA integrates with host DNA - it may interfere with control of cell division in basal cells - malignant tumor develops
