1. ¹Department of Biological Sciences, Hunter College of The City University of New York, New York, NY, USA
2. ²Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

Correspondence: Dr DA Foster, Department of Biological Sciences, Hunter College of the City University of New York, 695 Park Avenue, Room 927, New York, NY 10021, USA. E-mail: foster@genectr.hunter.cuny.edu

Received 20 July 2007; Revised 25 September 2007; Accepted 14 October 2007; Published online 12 November 2007.

Abstract

Loss of the von Hippel-Lindau (VHL) tumor suppressor gene contributes to proliferative disorders including renal cell carcinoma. The consequence of VHL loss is increased levels of hypoxia-inducible factor- (HIF), which is targeted for proteolytic degradation by the VHL gene product pVHL. HIF is a transcription factor that increases the expression of factors critical for tumorigenesis in renal cell carcinoma. We report here another regulatory component of HIF expression in renal cancer cells. Phospholipase D (PLD), which is commonly elevated in renal and other cancers, is required for elevated levels of both HIF1 and HIF2 in VHL-deficient renal cancer cells. The induction of both HIF1 and HIF2 by hypoxic mimetic conditions was also dependent on PLD in renal cancer cells with restored pVHL expression. The effect of PLD activity upon HIF expression was at the level of translation. PLD activity also provides a survival signal that suppresses apoptosis induced by serum deprivation in the renal cancer cells. Suppression of HIF2 has been shown to reverse tumorigenesis with renal cancer cells. The finding here that HIF2 expression is dependent on PLD in renal cancer cells suggests that targeting PLD signals may represent an alternative therapeutic strategy for targeting HIF2 in renal cancers where HIF2 is critical for tumorigenesis and elevated PLD activity is common.