-Inhibition of Histone Deacetylation

This paper reviews current research on G1 phase progression in human cancer. The effects of mutations in cyclins, cyclin dependent kinases, as well as p53 and Rb pathways on cancer onset is also examined. A major regulatory role in G1 phase progression involves extracellular signaling which activates the introduction of the first G1 phase cyclins in the cell. The induction of this early event is important in the completion of later events. If any of the G1 phase cyclins, cyclin dependent kinases, or regulatory pathways responsible for cell cycle control are affected by mutations, abnormal cellular proliferation and cancer is probable.

The eukaryotic cell cycle is a complex system of checks and balances that ensure the fidelity of cellular proliferation. Over the past few years, there has been considerable interest in the G1 phase of th

The Rb pathway is also critical in regulating the G1 phase. Rb is a tumor suppressor gene that controls gene expression necessary for DNA synthesis (S phase). In its hypophosphorylated state, Rb recruits histone deacetylase, a transcriptional repressor, and binds to E2F constraining transcription activity. Phosphorylation of Rb by the cyclin D kinases relieves this repressive state, freeing E2F. Free E2F stimulates cyclin E-cdk2 , which then acts through a positive feedback loop to facilitate progressive rounds of Rb phosphorylation and E2F release. Cyclin E-cdk2 phosphorylates p27 targeting it for destruction in proteasomes. Interestingly, once cells enter the S phase, cyclin E is targeted by ubiquitin mediated proteolysis by its catalytic counterpart, cdk2.

Cyclin dependent kinase inhibitors regulate cylin dependent kinase activity. Cyclin dependent kinase inhibitors can be classified into two families according to their structure and kinase targets. In inhibiting cyclin dependent kinases, cyclin dependent kinase inhibitors act to induce cell cycle arrest in response to inhibitory signals. Inhibitory signals include the arrest of the cell cycle in G1, in response to extracellular signals (INK4), or DNA damage (CIP/KIP). The INK4 family of proteins includes p16, p15, p18, and p19. INK4 proteins hinder the assembly of cyclin D with their kinase counterparts by binding to cyclin dependent kinases 4 and 6 arresting the cell cycle in G1. The CIP/KIP family of inhibitory proteins act o inhibit cyclin dependent kinase 2 from binding to cyclin E arresting the cell cycle. Interestingly, ongoing research of cyclin dependent kinase inhibitors has revealed that the cyclin dependent kinases 4 and 6 are activated by the CIP/KIP family of inhibitors. In this sense cyclin dependent kinase inhibitors act as both "positive and negative regulators of G1 phase progression."

Some topics in this essay:
Conclusion Abstract, G1 CIP/KIP, E- CDK2, Current Research, Discussion Conclusion, cyclin dependent, CIP/KIP INK4, Cyclin E-cdk2, dependent kinases, cell cycle, cyclin dependent kinases, Free E2F, g1 phase, dependent kinase, cyclin dependent kinase, dependent kinase inhibitors, kinase inhibitors, Phosphorylation Rb, cyclins cyclin, Kinase Inhibitors, rb pathway, cyclins cyclin dependent, human cancer, dna damage, g1 phase progression,