G1S transition

Enzyme synthesis

Transition from G1 to S phase involves assembly and activation of transcription factors allowing the synthesis of enzymes required for DNA replication. At the heart of this process are Rb-type proteins and the 'Rb pathway' as seen in the second figure. The retinoblastoma protein, Rb, and the related p107 and p130 proteins, bind to a number of transcription factors. These activate genes required for progression through S-phase, such as DNA polymerases and nucleotide kinases.

Progression through G1 requires the phosphorylation of Rb-type proteins, allowing the release of transcription factors and subsequent S-phase entry. Phosphorylation of Rb-type proteins is controlled primarily by the cyclin-D-dependent kinases, CDK4 and CDK6. Kinase activity is regulated by fluctuating levels of D cyclins and CKIs from the p16INK4 and kip families, particularly p16 itself.

Timing of transition

Exactly when a cell embarks on a G1-S transition is tightly controlled to ensure survival, with factors such as cell size, metabolic state, growth factor availability, and DNA damage affecting whether a transition takes place. Not all signaling pathways involved have been unravelled. However, cyclin-D synthesis and subsequent activation of CDK4/6 has been linked to growth factor availability. It is suggested that cyclin D acts as a cellular sensor with cyclin synthesis allowing cells to cycle in the presence of appropriate mitogens.

Pathways

Superimposed over cyclin/CDK systems are pathways to detect problems such as DNA damage and cell growth inhibition. The most important is the p53 pathway, which plays a key role in G1 arrest, apoptosis, and genomic stability. Cells exposed to DNA-damaging agents often become arrested in G1 in a p53-dependent manner. p53 activation increases transcription and therefore protein levels of p21, a CKI that blocks cell cycle progression via its ability to inhibit Cdk enzymes. p53 upregulation does more than induce G1 arrest; in many cases programmed cell death or apoptosis is seen. G1-phase arrest and apoptosis are very divergent responses; the mechanisms involved in determining which of these dominates is still largely unknown. Variables such as the extent of DNA damage and levels of p53 may play a role.

p53 is the most commonly mutated gene in human cancer—not surprising since loss of control of genomic stability is central to cancer development and p53 is a critical factor in monitoring genomic integrity.

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