Hif Von Hippellindau Disease And Other Neoplasms

von Hippel-Lindau (VHL) is a hereditary cancer syndrome, where patients develop a variety of highly vascu-larized tumors, such as renal clear-cell carcinoma, retinal angioma, CNS hemangioblastoma, and pheochromocy-toma (Kondo and Kaelin 2001). pVHL, the protein product of the VHL gene, interacts through its a domain with elongin B, elongin C, Cul2, and Rbx1 to become an E3

ubiquitin ligase (Krek 2000). As stated above, this multiprotein complex targets HIFa subunits for proteosome-mediated degradation. Mutations within the p domain of pVHL disrupt its interaction with HIFa subunits, leading to constitutive a-subunit stabilization and activity in VHL tumors. Renal tumor cell lines deficient in pVHL exhibit constitutive HIF function under normoxic conditions and high levels of expression of HIF target genes such as erythropoietin, VEGF, glucose transporters, and glycolytic enzymes.

Thus far, studies correlating loss of pVHL function with HIF dysregulation have been conducted in tumor-derived cell lines with a number of genetic abnormalities. Although reintroduction of pVHL into renal carcinoma cells eliminates their tumorigenic phenotype, this occurs within a cellular background including a number of genetic lesions. Therefore, we have eliminated murine Vhl from mouse ES cells, a primary cell line. We demonstrated that loss of pVHL is sufficient to completely deregulate HIF stabilization, DNA-binding activity, target gene activation, and nuclear localization, conferring a hypoxic phenotype to normoxic VhV/- ES cells (F. Mack et al., in prep.). Surprisingly, teratomas derived from VhV/- ES cells injected into immunocompromised mice exhibit smaller volume as compared to Vhl+- control tumors. These results suggest that other genetic changes must occur to facilitate tumorigenesis in the absence of Vhl. It has been hypothesized that HIF protein stabilization, HIFa transit to the nucleus, interaction with tran-scriptional co-activators, and DNA binding are all regulated by O2 availability. Our results argue that if this is the case, all of these steps must be downstream of pVHL. It will be important in the future to determine what other genetic lesions are necessary to confer a fully transformed neoplastic phenotype to pVHL-deficient cells.

Other tumor suppressor genes have been reported to regulate HIF function. For example, high levels of HIF-1a protein have been detected in glioblastoma and prostate cancer cells with mutations in the tumor suppressor PTEN (Zhong et al. 2000; Zundel et al. 2000) and colon cancer cells deficient in p53 (Ravi et al. 2000). When challenged by hypoxic stress, cells frequently undergo cell cycle arrest and/or apoptosis (Graeber et al. 1996; Gardner et al. 2001). It has been proposed that hypoxia can stimulate p53 protein stabilization (Graeber et al. 1994). In fact, this may occur by direct association with the HIF-1a protein (An et al. 1998). These results suggest a model whereby hypoxia induces p53 which ultimately down-regulates HIF-1 a by recruiting mdm-2-as-sociated ubiquitinization machinery (Ravi et al. 2000). However, we have closely examined multiple human cancer cell and ES cell lines and found that hypoxia alone is not sufficient to elevate p53 protein levels (Y. Pan and M.C. Simon, in prep.). Furthermore, the expression of p53 decreases under anoxic conditions, presumably due to a general inhibition of translation in cells starved for O2. Our studies suggest that hypoxia per se is not a bona fide stimulus of p53 stabilization. We propose that the p53 pathway is activated in hypoxic regions of tumors via secondary effects brought by hypoxia and lack of proper vascularization. Further investigation of the mechanisms leading to p53 accumulation in hypoxic tumors should help provide a framework for understanding its role in regulating tumor angiogenesis.

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook

Post a comment