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RB (Cell cycle control, Many cancers deregulate RB phosphorylation, RB…
RB
Cell cycle control
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In late G1, CDK4 (or CDK6) bound to cyclin D phosphorylate RB- commits cells to leave G1 & progress through cell cycle - referred to as the "restriction point"
Cyclin D is expressed in response to mitogens - RB therefore couples cell cycle entry to mitogenic signals - "Gatekeeper of the cell cycle"
In S phase, CDK2 is activated by cyclin E phosphorylates additional sites in RB
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As long as RB is unphosphorylated, cells stay in G1 or become quiescent (G0) or senescent
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Mitogens -> expression of cyclin D -> activation of CDK4 & 6 -> phosphorlates RB -> inactivates gatekeeper function -> S phase -> Cyclin E activates CDK2 -> Additional phosphorylation of RB
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RB binds & inhibits E2F
E2F family bind and regulate genes involved in DNA replication & cell cycle progression e.g. cycin E gene
E2F binds promoters of target genes & then uses its txn actn domain to recruit TFIID to promoters -platform for other txn factor asembly
TFIID recruitment is rqrd 4 txn of protein-coding genes, but is inefficient -assistance by txn activators such as E2F accelerates a rate-limiting step
RB pocket binds t o txn activation domain that E2F uses to recruit TFIID & masks txn actn domain of E2F, RB blocks txn activation that RB would confer.
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Discovery
Discovered as the tumour supp. inactivated in retinoblastoma, a rare cancer of the retina
Inheritance of one inactive Rb allele gives a 90% chance of retinoblastoma by 6yrs of age, after somatic mutn of 2nd allele
95% cure rate, but survivors are predisposed to sarcomas later in life, after loss of 2nd Rb allele.
Somatic mutn of both Rb alleles is common in many tumour types e.g. almost all small cell lung cancers
CDK4/6 inhibitors
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Many patients suffer neutropenia (depletion of neutrophils) & increasd susceptibility to infection - anemia also common
Cancers eventually become resistant to palbociclib, sometimes due to decreased expression or mutation of RB
Recruits HDACs & DNMTI
When bound E2F, RB recruits histone deacetylases (HDACs) & DNA methyltransferase (DNMT) 1 to repress E2F target genes
DNA methylation occurs at CpG sites, that are common at mammalian promoters
CpG methylation blocks binding by some TFs e.g. MLL1 histone methyltransferase that marks active promoters with H3K4me3
Histone deacetylation reduces accessibility of DNA & removes marks that recruit TFs with bromodomains e.g. TFIID
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RB protein structure
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Several DNA tumour viruses encode oncogenic proteins that neutralise RB by binding a cleft in the pocket e.g. E7 protein of human papillomavirus (HPV)
Cervical cancers usually have WT Rb genes, but the protein is neutralised by E7
N terminal domain = resembles pocket. Rest of RB = unstructured & flexible
C terminal region = bound by prtein phosphatase I (PP1) & cyclin-dep kinases CDK2,4 & 6