Ubiquitin-dependent proteolysis in G1/S phase control and its relationship with tumor susceptibility.
Cell division depends upon the coordinated action of positive and negative regulatory factors that ensure high fidelity replication of the genome and its equivalent separation into daughter cells following cytokinesis. The role of positive factors such as the cyclin dependent kinases in promoting cell division is firmly established, as is the function of CDK inhibitors and phosphatases that antagonize CDKs. In addition to these, regulated protein destruction is now appreciated as essential for temporal regulation of cell cycle transitions. Protein degradation serves as an irreversible switch that ensures temporally regulated cell cycle transitions. Signal-dependent regulation of protein degradation is best understood with regard to the 26S proteasome. Proteins are directed to this machine subsequent to enzymatic transfer of a highly conserved small polypeptide, ubiquitin. The focus of this review is the regulatory molecules that direct the regulated attachment of ubiquitin, polyubiquitylation, to proteins destined for degradation as cells transition through the G1 phase into S-phase. During the past decade, it has become increasingly apparent that these molecules are critical mediators of normal cell proliferation and as such they are frequently deregulated in human cancers.
Abramson Family Cancer Research Institute, Department of Cancer Biology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
J Alan
JA
Diehl
Bhaskar
B
Ponugoti