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#Cyclin E

2 public questions tagged with this topic.

Cell Cycle Regulation

Which of the following is a G1-phase Cyclin?

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.

Ref: Sherr & Roberts, D-Type Cyclins as Mitogen Sensors and G1 Progression, Genes Dev 1999; Alberts, G1 Cyclins Biology.

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Cell Cycle Regulation

Which Cyclin-CDK complex is responsible for the G1/S transition?

Transition from growth phase G1 into DNA synthesis S phase requires activation of gene expression program and licensing factor conversion. In early G1, Cyclin D-CDK4/6 partially phosphorylates Rb after mitogen stimulation allowing limited E2F activity producing Cyclin E. Cyclin E accumulation reaches zenith in late G1 forming active kinase with CDK2. Cyclin E-CDK2 completes hyperphosphorylation of Rb at distinct sites including Ser612 Ser807, fully dissociating Rb from E2F1-E2F3 activators. Liberated E2F-DP heterodimers bind promoters with TTTCCCGC motifs driving transcription of replication genes such as Cyclin A, dihydrofolate reductase, thymidylate synthase, PCNA, Cdc6, CDT1, MCM helicase subunits and DNA polymerase alpha delta epsilon. Simultaneously Cyclin E-CDK2 phosphorylates Kip1 inhibitor p27 at Thr187 creating phosphodegron for SCF-Skp2-Cks1 ubiquitination and degradation, eliminating CDK2 inhibition. It also phosphorylates Treslin TICRR and RecQL4 facilitating Cdc45-MCM-GINS helicase activation for origin firing. Expression transient because SCF-Fbw7 targets autophosphorylated Cyclin E for destruction, restricting activity window. Amplification frequently observed in ovarian and breast cancers driving replication stress and genomic instability. Additional feedback loops involving polo-like kinases, phosphatases and SCF-mediated degradation reinforce irreversibility and protect against premature progression that would compromise genome integrity and viability.

Ref: Hinds, Cyclin E-CDK2 Complex and G1/S Transition Control, Cell Cycle 2002; Alberts et al., Chapter 17, G1/S Regulator.

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