Projects

The cyclin-dependent kinases (Cdks) act as switches that control cell-cycle progression by alternating between active and inactive states. Cdks are activated by binding to cyclin proteins and also by phosphorylation.

Mutations of the p53 tumor supressor are among the most frequently observed genetic alterations found in cancer. Cellular p53 levels increase in response to DNA damage, resulting in either cell-cycle arrest or cell death via apoptosis.

The Smad family of proteins mediate TGF-beta signaling from the cell membrane to the nucleus, propagating the signal by the formation of homo- and hetero-oligomers and by cooperating with other transcription factors to regulate the expression of genes.

Mutation of the von Hippel-Lindau tumor supressor (VHL) is associated with the majority of renal carcinomas and also with VHL syndrome. In the cell, VHL regulates the degradation of HIF-1 and the levels of vascular angiogenic growth factor (VEGF-1).

The PTEN phosphatase is found mutated in a diverse set of human cancers and is implicated in hereditary cancer disposition syndromes. PTEN can act on both peptide and phosphoinositide substrates (in vitro).

Heat-shock protein 90 (HSP90) is a cellular chaperone protein required for the activation of several eukaryotic protein kinases, including the cyclin-dependent kinase CDK4. Geldanamycin, an inhibitor of the protein-refolding activity of Hsp90, has been shown to have antiproliferative and antitumor activities.

Histone deaceylases (HDACs) mediate regulation of gene expression via changes in nucleosome conformation. Deregulation of HDACs is associated with several cancers; while some inhibitors of HDACs have been shown to have antitumor effects, including induction of terminal differentiation and prevention of tumor formation in animal models.