The regulation of neoplastic transformation, mRNA turnover, and the adaptive response to hypoxia are each of profound biologic and clinical importance. These apparently distinct cellular events are linked through the function of a single protein, the Von Hippel-Lindau (VHL) gene product, pVHL. Renal cell carcinomas (RCC) associated with VHL mutations exhibit increased expression of Glucose Transporter 1 (GLUT 1) and Vascular Endothelial Growth Factor (VEGF) mRNA, which results from increased mRNA stability and transcription. The interaction of the VHL gene product, pVHL, with elongin B, C, Cu12, and Rbx-l has conclusively demonstrated a role of this complex (VBC) in regulating protein turnover. However, the absence of pVHL in RCC cells has also been associated with activation of the phosphatidylinositol 3 (PI 3)-kinase pathway, and disordered fibronectin (FN) assembly. Neither observation accounts for the increased stability of hypoxia-inducible (VEGF and possibly GLUT1) mRNA observed with pVHL-deficient RCC lines. We have made four observations that potentially identify mechanism(s) of increased GLUT1 mRNA stability in pVHL deficient RCC cell lines: i) The GLUT1 3'UTR alters gene expression in a pVHL-dependent manner; ii) pVHL specifically regulates the expression of hnRNP A2, which binds the GLUT1 3'UTR; iii) Regulation of hnRNP A2 levels by pVHL requires functioning proteasomes; iv) pVHL regulates p38 Stress-Activated Protein Kinase (SAPK) activation, which modulates VEGF and other AURE-dependent mRNA turnover. We hypothesize that the absence of pVHL results in the activation of the p38 SAPK pathway and hnRNP A2 overexpression and propose to address this and its relevance to GLUT1 mRNA turnover.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA095539-05
Application #
7046099
Study Section
Special Emphasis Panel (ZRG1-PTHC (01))
Program Officer
Perry, Mary Ellen
Project Start
2002-04-22
Project End
2007-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
5
Fiscal Year
2006
Total Cost
$274,631
Indirect Cost
Name
Dartmouth College
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Nichols, Ralph C; Botson, John; Wang, Xiao Wei et al. (2011) A flexible approach to studying post-transcriptional gene regulation in stably transfected mammalian cells. Mol Biotechnol 48:210-7