LEC53: Tumor Suppressors Flashcards Preview

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Flashcards in LEC53: Tumor Suppressors Deck (32):

what experimentally suggests tumor suppressors exist?

1) when fused a normal and tumor cell in lab, phenotype was of normal cell; this means tumor suppressors must exist

2) cancer susceptibility can be inherited, which wouldn't make sense re: oncogenes, since there are events cause susceptibility to oncogene expression to occur


what about inherited syndromes tells us about tumor suppresor genes?

there are multipkle inherited syndromes that confer hereditary susceptibility to particular tumor types; are consistent w/ existence of tumor suppressor genes 



what are examples of inherited syndromes that confer hereditary susceptibility to paticular tumor types / what are their associated genes? 

familial retinoblastoma - pRb 

Wilms' tumor of kidney - Wt1

hereditary breast cancer - BRCA1, BRCA2 

hereditary melanoma - p16, p15


what is inheritance pattern of susceptibility to tumor formation?

mendelian dominant 

but not all who have inherited defective gene get cancer because of incomplete penetrance


do inherited susceptibility to particular tumor types tend to be linked w/ single types of cancer, or more general?

single types of cancer 

EXCEPTION THOUGH: LI-FRAUMENI SYNDROME, p53 mutation, results in increased susceptibility to many kinds of tumors


what are DNA tumor viruses

contain novel oncogenes within their genomes that don't have cellular counterparts 

i.e. SV40, HPV


what is SV40, how does it work?

DNA tumor virus, simin virus 40 

expresses a laretumor antigen - T antigen - that binds cellular p53 and pRb and thereby inactivates them 




what is HPV, how does it occur?

DNA tumor virus, human papilloma virus 

makes 2 proteins: e6 and e7

e6 targest p53 for degredation; e7 inactivates pRb

associated w/ almost all human cervical cancer, and some head and neck cancers 


where does familial vs. sporadic retinoblastoma occur?

familial: both eyes, involves secondary non-ocular tumors

sporadic: one eye, not associated w/ secondary tumors


what does mutation in Rb predispose someone to?

retinal cancer, and sometimes osteosarcoma if it's familial - bone cancer


what is knudsen's 2 hit hypothesis? what does it explain re: retinoblastoma?

explains difference in manifestation of familial vs. sporadic inheritance of Rb cancer, where familial -> bilateral disease and sporadic -> unilateral disease 

familially inherited retinoblastoma ppl begin w/ 1 mutant Rb allele in all retinal cells, so only takes 1 somatic mutation to get 2 mutant Rb gene copies in all cells 

vs. sporadic retinoblastoma, needs to get 1 mutant Rb allele developed, then another somatic mutation to get 2; this is a rarer event, so unifocal disease results


what is different about what is required to activate an oncogene vs. tumor suppressor? and what is mutation result?

oncogene: single allele mutation event creates gain of function mutation -> cell transformation 

tumor suppressor: mutation required on both alleles, causes loss of function -> cell transformation 


what does Rb do?

it inhibits E2F, which is a gene regulatory protein that controls entry into S phase 

thus Rb controls entry into S phase




mechanisms for tumor suppressor genes loss in human cancer?

1) deletion 

2) missense mutation 

3) frameshift muation 

4) haplounsufficiency


what type of mutation does gene for p53 usually have?

missense muation 


what is p53 function? when is it upregulated?

p53: tumor suppressor, involved in cellular response to DNA damage. it is a txn factor that binds to DNA, recruits coactivators to alter gene expression 

p53's upregulated through a disruption of its interaction w/ mdm2, the Ub-ligase 



what does a mutational spectrum of p53 show?

shows each residue of the p53 protein (393 aa in p53), plots number of mutations at each residue 

see frequency of alterations are clustered in evolutionarily conserved domains, "hot spots" 



where on p53 are mutations?

6 hot spots that correspond to the central domain of the protein, where it binds to DNA - the DNA-binding domain 

R175, G25, R248, R249, R273, R282 are the hot spots

R248 adn R273 directly contact DNA; remaining hot spots play role in structure pf 53 to allow these contacts w/ DNA


are hot spots the same in all cancers?


different carcinogens are associated w/ different hot spots 


what are p53's functions re: oncogenes?

1) cause cell cycle arrest: oncogene activation by proteins like Myc, Ras, E1a leads to upregulation of ARF; ARF inhbits Mdm2, thereby upregulating p53

2) cause apoptosis by upregulation as a txn factor, of target genes like p21 - a cdk inhibitor-  or PUMA and Noxa - apoptosis promoters


what does p53's persistence in cancer state suggest?

rather than being deleted altogether, p53 is mutated by missense mutation in cancer state

suggests that p53 muation doesn't merely cause LoF; p53 in its mutated form may also confer additional activities that're important for cancer progression


what causes a frameshift mutation?

what is result of a frameshift?

1 or 2 base insertions of deletions 

changes the reading frame of a gene 

results in expression of a truncated protein, and a STOP codon within ~30 bases


what is most common type of mutation for most oncogenes?

for p53: missense 

for others: frameshift


what is APC, adenomatous polypopsis coli protein? its function in healthy vs cancer state?

tumor suppressor gene 

HEALTHY: In Wnt pathway, APC binds to beta-catenin, targets beta-catenin for degredation by phosphorylating it, SCF ubiquitin ligase destroys it, keeps beta-catenin levels low & prevents tumor

CANCER: APC frameshift mutation results in truncated protein, it cannot bind to B-catenin, B-catenin get tumor formation


what happens to pRb to cause cancer?

usually deletion


what is Loss of Heterozygosity?

when there's a missense or frameshift muation of 1 allele of a tumor suppressor, the remaining WT allele is deleted


what does haploinsufficiency differently require for tumor suppressor inactivation?

only 1 hit, not 2 hit- only 1 allele needs to be altered for haploinsufficiency to manifest


what are the mechanisms of haploinsufficiency?

1) reduced expression 

2) dominant negative effects 

3) transcriptional silencing


what is "reduced expression" method of haploinsufficiency?

mutation of 1 allele can result in reduced expression of that allele as the tumor suppressor protein 

if need a certain amount of tumor suppressor protein for good functioning, it may not be sufficienct if it's mutated

causes loss of growth control


what is "dominant negative effect" method of haploinsufficiency?

what is required?

occurs when 1 allele is mutated, the other is WT, and mutant allele in complex w/ WT results in mutant inhibiting the action of the WT protein or otherwise poisoning it

only relevant for an active mutated allele, not a deleted allele - altered allele must be making something for this effect


what is "transcriptional silencing" method of haploinsufficiency?

how might it occur?

when 1 allele is inactivated by mutation and remaining WT allele isn't expressed b/c silenced through some epigenetic means

i.e. promoter methylation of WT allele -> silencing

net effect: no expression, even though looks like a normal and a mutated allele when look at the DNA


why are cancer genes like BRCA1 called "susceptibility genes"?

b/c they have incomplete penetrance - presentation of inherited bad copy of allele doesn't mean disease state will result

penetrance in this case is highly variable

thus cannot tell woman with certitude what to do if she is a carrier of BRCA1 mutation- like angelina jolie

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