Role of Ink4a/Arf Locus in Beta Cell Mass Expansion under Physiological and Pathological Conditions
Figure 2
(a) Cell cycle regulation by /. inhibits CDK4/6 activity, preventing RB phosphorylation, thus preventing G1/S transition. Inactivation of CDK4/6 promotes Rb/E2F1 association down-regulating transcription of E2F1 target genes, which would trigger G1/S transition. inhibits MDM2 activity thereby stabilizing p53 and promoting beta cell senescence. (b) Regulation of beta cell Cdkn2a locus. Binding of PRC1 and PRC2 complex proteins to the p16/p14ARF promoter results in formation of heterochromatin leading to suppression of transcription. HDACs also repress Cdkn2a locus but they conform a regulatory feedback loop: release of E2F1 which up-regulates leading to an inhibition of Mdm2 and inducing senescence through p21-p53 pathway. Betatrophin promotes beta cell proliferation by inhibiting Cdkn2a and increasing expression levels of cyclins and E2F1 (through a still unknown mechanism). lncRNA ANRIL, transcribed from the Cdkn2a locus, directly binds to the transcript and also recruits the PRC complexes to repress the transcription of genes at this locus. ANRIL is induced by E2F1 after DNA damage. (c) Cdkn2a locus showing exons of / genes involved in alternate splicing. Promoter regions are shown in green.
