MERIT Award Recipient: Michele Pagano, M.D.
F-Box Proteins: Deregulated Cell Cycle Control and Proteolysis in Cancer
The eukaryotic cell can be considered an ensemble of highly networked molecular machines. The ubiquitin-proteasome system (UPS) rapidly degrades the modular regulatory components of these machines and, in doing so, contributes to the timely synchronization of the cellular gears. Substrates of the UPS include tumor suppressors, oncoproteins, cell cycle regulators, transcription factors, and receptor tyrosine kinases, amongst others. In addition to genetic alterations, aberrant proteolysis of cellular regulators contributes significantly to tumorigenesis and genomic instability. Therefore, the implications deriving from the study of the UPS are far-reaching, as evidenced by the therapeutic value of proteasome inhibitors in cancer.
The sequential activation of different cyclin-dependent kinases (CDKs) plays a central role in controlling the passage through the different phases of the cell cycle and, consequently, cell proliferation. Work in the Pagano laboratory has elucidated the molecular and cellular mechanisms by which three ubiquitin ligase complexes (SCFSKP2, SCFβTRCP, and APC/CCDH1) control cell cycle progression via the degradation of cancer-relevant substrates that regulate the activity of CDKs. Importantly, this work has revealed that altered degradation of CDK regulators occurs in many types of cancer. In particular, it was found that the destabilization of the CDK inhibitor p27 is a reliable marker of poor prognosis in patients with carcinomas and lymphomas. Although transformation has been shown to often involve the inactivation of some CDK inhibitors by direct mutation, mutations and homozygous deletions of the CDKN1B gene encoding p27 are extremely rare in human tumors. Results from Dr. Pagano's laboratory suggest that the low expression of p27 observed in human carcinomas is often caused by enhanced UPS-mediated degradation of p27 rather than altered CDKN1B gene expression. Significantly, they found that the F-box protein SKP2 targets p27 for degradation by the UPS and that the expression of SKP2 inversely correlates with p27 levels in human breast cancers and lymphomas. Additionally, SKP2 cooperates with activated RAS in a mouse model of lymphomagenesis. These findings, together with others in the literature, indicate that SKP2 is the product of a proto-oncogene.
Dr. Pagano and coworkers will investigate the mechanisms by which SKP2 accumulates in cancer cells. In addition, they will study the cell cycle function of the related F-box protein EMI2 and identify its biologically significant substrates. As the mechanisms behind the ubiquitin-mediated proteolysis of cell cycle regulators are unraveled, this group is committed to the integration of its basic research results with an understanding of malignant transformation in human disease.