Functional Analysis of the VHL Tumor Suppressor Gene

Project: Research project

Project Details


DESCRIPTION: (provided by applicant) Approximately 30,000 Americans will
develop renal cancer this year and nearly 12,000 will die from the disease.
Mutation and/or inactivation of the von Hlippel about Lindau (VHL) gene occurs
as an early, initiating event, promoting the development of most renal cell
carcinoma (RCC). We have demonstrated that the binding of Elongins B & C
protects VHL proteins from proteasomal degradation, in a manner similar to SOCS
(suppressor of cytokine signaling) protein/elongin complexes. Expression of
exogenous VHL gene product(s) in a renal cancer cell line (lacking wild type
VHL) influences the growth and differentiation properties of confluent cells
grown on extracellular matrix (ECM). In addition, VHL protects these cells from
apoptosis. In accord with the function of VHL to inhibit apoptosis and suppress
stress-related signaling pathways (e.g., hypoxia), our observation that VHL
utilizes internal translation to synthesize a functional protein suggests a
mechanism to assure adequate levels of VHL protein under conditions of
suppressed cap-dependent translation. Taken together, these findings suggest
the hypothesis that VHL may function as a tumor suppressor by suppression of
stress signals (SOSS) through modification (e.g., ubiquitination) of key
regulators of pathways involved in cell-cell, cell-ECM and stress-related
signaling. The aims of this project are: (1) To determine the mechanism of
VHL-mediated protection from apoptosis by assaying specific regulators of
apoptosis common to UV irradiation, serum starvation, and glucose deprivation.
We will also evaluate the pro-apoptotic potential of specific mutations in VHL
and investigate whether these mutations drive apoptosis and provide selective
pressure toward cells that are able to escape apoptosis; (2) To investigate the
mechanism and functional imnportance of translational and post-translational
regulation of VHL; (3) To identify potential targets of VHL activity,
VHL-associating proteins will be compared under conditions of cell stress, low
and high cell density and on plastic and ECM.
Effective start/end date2/27/021/31/08


  • National Cancer Institute: $296,086.00
  • National Cancer Institute: $296,131.00
  • National Cancer Institute: $289,082.00


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