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Approximately 80% of renal cell carcinomas (RCCs) have clear-cell histology—that is, cells appear clear under a microscope.5 In the majority of clear-cell RCCs, the von Hippel-Lindau tumor suppressor gene (VHL) is inactivated through means such as deletion or other genetic mutation.2
Under normoxic conditions, the VHL protein (pVHL) closely regulates hypoxia-inducible factor-1α (HIF-1α) by causing its rapid degradation, so that HIF-1α is not normally found in the cell. As a result, HIF-1α is unavailable to bind to the corresponding subunit, HIF-1β, and the subsequent cascade of cellular signals does not occur.4 In contrast, under hypoxic conditions, pVHL regulation of HIF-1α is impaired. As a result, HIF-1α is not degraded. The resulting accumulation of HIF-1α within the cell is responsible for the high degree of vascularity commonly seen in VHL-deficient tumors.4 A critical consequence of VHL inactivation is upregulation of vascular endothelial growth factor (VEGF) via a pathway involving accumulation of HIF-1α.3,4,6
Recent research also indicates that VHL silencing results in defects in a process called ubiquitination, in which cellular proteins (in this case, HIF-1α) are tagged for degradation with molecules known as ubiquitins.3 Impairments in the ubiquitination pathway lead to the accumulation of HIF-1α within the cell, even without hypoxic conditions.4 (For more information on ubiquitination, click here.)
HIF-1α is a key transcriptional factor in the molecular pathway of hypoxia and regulates the expression of a number of genes whose products are critical to tumor angiogenesis, proliferation, survival, and metabolism. With respect to angiogenesis in RCC, one of the most important gene products downstream of HIF-1α is VEGF.2-4,6
