Practice question

Distinct cyclin classes act in sequential waves. G1 cyclins link extracellular cues to cell cycle commitment. D-type cyclins D1, D2, D3 family are primary mitogen sensors. Upon signaling through Ras-RAF-MEK-ERK and PI3K-AKT leading to Myc and AP-1 activation, CCND genes transcribed. Cyclin D binds CDK4 and CDK6, kinases inhibited by INK4 family members p16, p15, p18, p19. Cyclin D-CDK4/6 complexes sequester Cip/Kip inhibitors p21 and p27 thereby facilitating CDK2 activation, and phosphorylate retinoblastoma protein Rb at specific residues distinguishing from Cyclin E mediated sites, reducing affinity for chromatin modifiers histone deacetylases and Suv39h1 and initiating derepression of E2F targets including Cyclin E. Unlike S and M cyclins destroyed by APC/C, Cyclin D levels strongly reflect growth factor availability because GSK3beta phosphorylation targets it for SCF mediated proteolysis upon mitogen withdrawal leading to rapid disappearance and cell cycle exit to G0. Amplification of CCND1 occurs frequently in mantle cell lymphoma due to translocation, breast and head neck cancers, and drives dependence on CDK4/6 activity targetable by inhibitors palbociclib ribociclib abemaciclib.