Current Research

Hsp90

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, VEGF 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.

 
Kidney Cancer
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. 

 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. 

Simplified representation of the kidney cancer gene pathways

Birt-Hogg-Dubé (BHD) &
Tuberous Sclerosis Complex (TSC) Syndromes

Germline mutations in the tumor suppressor gene FLCN cause Birt-Hogg-Dubé (BHD) syndrome, which shares many phenotypic manifestations with Tuberous Sclerosis Complex (TSC) due to TSC1 or TSC2 mutations. The exact molecular function of FNIP1/2 (binding partners of Flcn)  and Tsc1, however, had remained elusive. Our work demonstrated that FNIP1/2 and Tsc1 are new co-chaperones of Hsp90. This research establishes an active role for Tsc1 and FNIP1 as facilitators of Hsp90-mediated folding of kinase and non-kinase clients – including Tsc2 and FLCN – thereby preventing their ubiquitination and degradation.

Current literatures describe FNIP1/2 and Tsc1 as negative regulators of AMPK/mTOR signaling. As a consequence, the vast majority of the field has focused solely on this single pathway, where as we have demonstrated the ubiquity of FNIP1/2 and Tsc1 across a variety of signaling pathways. In fact it is likely their roles as suppressors of mTOR are a function of their roles as Hsp90 co-chaperones.

 

Understanding the independent roles of FNIP1/2 and Tsc1 will aid in the development of targeted therapies for tuberous sclerosis and Birt-Hogg-Dubé syndromes alone or in concert with Hsp90 inhibitors.

 

 

mollapom@upstate.edu

(315)464-8749

Departments of Urology &

Biochemistry and Molecular Biology

Upstate Medical Univeristy

766 Irving Ave

Syracuse, NY 13210