E2

Figure 15.6 The VHL ubiquitin ligase complex See text for further explanations.

E3 ubiquitin ligase that degrades TP53 and its function is mimicked by the HPV E6 oncoproteins (^5.3). The SCFSKP2 E3 ubiquitin ligase mediates the degradation of p27KIP1 that relieves the inhibition of the CDK2/Cyclin E holoenzyme at the end of the G1 phase and allows progression of the cell cycle into S phase (^6.4). Overexpression of either Cyclin E, SKP2, or MYC appears to increase its activity inappropriately in several human tumors (including renal carcinomas).

As far as we know, the main substrates of the VHL E3 ubiquitin ligase are two closely related proteins, HIF1a and HIF2a, where HIF stands for 'hypoxia-inducible factor'. Missense mutations in the VHL protein cluster in two regions, i.e., in one face that makes contact with the HIFa proteins and in the opposite face that interacts with the Elongins. The type of mutations inherited in the VHL gene bears some relation to the disease subtype. For instance, pheochromocytoma (i.e. type II VHL syndrome) is only found in patients with certain point mutations, such as 505C>T or 712C>T. In contrast, insertion and deletion mutations (which would be expected to lead to frameshift mutations) increase the risk for RCC.

The HIFa proteins are transcription factors that induce a particular pattern of gene expression in response to low oxygen, i.e. during hypoxia (Figure 15.7). Under normal conditions, i.e. normoxia (^Box 9.1), HIF1a and HIF2a proteins undergo rapid turnover, with a half-life of a few minutes. The prevailing oxygen partial pressure is signaled through specific proline hydroxylases which hydroxylate one proline in the HIFa 'oxygen-dependent degradation domain' (ODD). These kind of enzymes belong to the EGLN family and are different from those involved in collagen biosynthesis, but likewise contain ferrous iron and require oxygen and 2-oxo-glutarate as cosubstrates. With its proline hydroxylated, the HIFa ODD domain is recognized by VHL and the HIFa proteins are ubiquitinated and targeted for degradation by the proteasome.

If the oxygen partial pressure decreases, the proline in the ODD domain remains non-hydroxylated and the HIFa proteins accumulate in the cytosol. They combine with HIF1P, also known as ARNT, which is the dimerization partner for several nuclear factors, including the dioxin receptor AhR. The HIFa/ARNT heterodimer enters the nucleus and binds to specific recognition sites in promoters to activate genes whose products help the cell adapt to low oxygen supply and to increase

Table 15.4. Some ubiquitin ligases important in human cancers

Ubiquitin ligase

Function

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