- In contrast to other cell cycle phases, extracellular signaling from growth factors/mitogens is essential for G1 phase progression. These signaling pathways induce cyclin D expression and its assembly to its catalytic subunits CDK4 and CDK6.
- Since D-type cyclins have a short half-life, the continuous presence of growth factors/mitogens is required until the cell passes through the restriction point.
- The activation of holoenzyme cyclin D-CDK4/cyclin D-CDK6 is a complex process and requires phosphorylation/dephosphorylation of CDK4 and CDK6 and assembly factor p21.
- Active cyclin D-CDK4/6 holoenzyme phosphorylates Retinoblastoma (Rb) proteins which is required for the dissociation of Rb interaction with E2F transcription factor.
- E2F is required for transcription of cyclin E and S phase genes. However, the phosphorylation of Rb by Cyclin D-CDK4/6 is not sufficient as the complete liberation of E2F requires hyperphosphorylation of Rb proteins which is mediated by Cyclin E – CDK2.
- Once Rb is hyperphosphorylated by Cyclin E – CDK2, Rb is no longer active and cell cycle progression becomes independent of growth factors/mitogens that correspond to the passage of restriction point. Remember that tumor cells have a compromised restriction point and can pass this in the absence of growth factors/mitogens.
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