Tumour Suppressors Flashcards
How do familial and sproadic forms of retinoblastoma differ?
hereditary - early onset, bilateral, multifocal tumours, autosomal dominant inheritance.
Sporadic - late onset, unilateral tumours.
How does Rb act as a gatekeeper?
Binds E2F, suppressing it and so blocking S phase entry.
Binds and recruits HDAC –> deacetylates nucleosomes –> chromatin compaction.
What are the preferences of pRb proteins and what consensus has been reached regarding their role?
RB1 - E2F, E2F2, E2F3 - activators.
p107 - E2F4, E2F5 - repressors
p130 - E2F4, E2F5 - repressors.
Rb needed for cell cycle exit, p107 and p130 for maintenance of arrest.
What happens to Rb during cell senescence?
It becomes hypophosphorylated as proteins preventing Rb phosphorylation accumulate. S phase entry is inhibited.
How do p27 and p21 induce Cyclin E activation?
How can cyclin E inhibition be rapidly induced?
They induce the assembly of CDK4/6-CyclinD complexes which they cannot inhibit. These provide a sink, sequestering the CKIs. Cyclin E inhibition is now reduced. Cyclin E can phosphorylate p27, targeting it for degradation.
p53 promotes rapid accumulation of p21 which then inhibits CyclinE-CDK2 complexes.
How can p16INK4A be linked to cancer?
What is its dual inhibitory mechanism?
It becomes induced in response to oncogenic Ras signalling - promotes senescence like growth arrest.
As well as inactivating CDK4, liberates sequestered CKIs which bind and inhibit CyclinE-CDK2.
What other cancers are associated with Rb loss?
Prostate, small and non-small cell lung carcinomas, mammary, osteosarcomas, bladder tumours.
How is Rb-associated with cervical cancers?
What is notable about Rb non-linked cancers?
Found in cervical cancers with no evidence of papilloma virus involvement but not in cancers associated with HPV E7.
Tumours retaining normal Rb often show other alterations in Rb pathway.
What mechanisms can lead to oncogene activation?
How does an oncogene differ to a proto-oncogene?
Activating mutations (RasG12D) Gene fusion (BCR-ABL) Gene Amplification (EGFR) Promoter exchange (Bcl-2) PO must be mutated or overexpressed to contribute to cancer development.
What additional function does RB have besides inhibiting E2F?
105 kDa nuclear phosphoprotein.
May control differentiation of retinoblasts (therefore possibly exit from cell cycle).
