Electron Microscopy reconstruction of the yeast vacuolar ATPase. Ribbon models for individual protein subunits have been fit to the electron density.
From the lab of Stephan Wilkens, PhD.
Mehdi Mollapour, PhD
Research Programs and Affiliations
- Biomedical Sciences Program
- Research Pillars
Education & Fellowships
- Fellowship: University of Sheffield, UK, 2007
- Fellowship: University of London, UK, 2003
- PhD: University of London, UK, 2001, Biochemistry
- National Cancer Institute, NIH, Bethesda, MD, 2007–2013
Post-translational regulation of the Hsp90 molecular chaperone machinery in cancer
Link to PubMed (Opens new window. Close the PubMed window to return to this page.)
Heat Shock Protein-90 (Hsp90) is a molecular chaperone critical to the folding, stability and activity of many proteins known as "client proteins" including many responsible for tumor initiation, progression and metastasis. This makes the chaperone Hsp90 an attractive target for cancer therapy. Hsp90 chaperone function is coupled to its ATPase activity. Small molecule inhibitors of Hsp90 bind to the ATP-binding pocket on Hsp90, which prevents its interaction with the client proteins therefore, leading to their degradation by the proteasome. In contrast to other anti-cancer drugs, Hsp90 inhibitors simultaneously inhibit multiple drivers of oncogenesis. Examples include Raf-1, HER2/ErBb2, VGEF receptor, DNA repair proteins, HIF1α and other regulators of the tumor growth, angiogenesis, metastasis and survival. Inhibition of Hsp90 therefore leads to simultaneous inhibition of a broad range of oncogenic pathways. Our work on post-translational modifications of Hsp90 has redefined the regulation of its chaperone activity and revealed the reciprocal regulatory mechanisms between the "kinase clients" and Hsp90. Our research currently focuses on dissecting this process in kidney cancer.
Worldwide nearly 338,000 people develop kidney cancer every year, and over 100,000 people die from the disease. Renal cell carcinoma (RCC) is the most common type of chemotherapy-resistant kidney cancer and it is distinguishable by histopathological features as well as the underlying gene mutations. The most common type of RCC, clear cell renal cell carcinoma (ccRCC), is closely associated with the mutations of the Von Hippel-Lindau (VHL) tumor suppressor gene that lead to stabilization of hypoxia inducible factors (HIF-1α and HIF-2α), which is critical for tumor growth and angiogenesis in both sporadic and familial forms of this disease. VHL also possess multiple HIF-independent functions.
Our laboratory uses a combination of cell-based assays, biochemical, biophysical assays, tumors derived from ccRCC patients and tumor xenografts to investigate the role of post-translational modifications of Hsp90 and its co-chaperones in chaperoning the signaling pathways that maybe involved in ccRCC initiation and progression.
SUNY Distinguished Professor Emeritus
- Richard Cross, PhD
- David Turner, PhD