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Figure 15.7 Structure and regulation ofHIFa proteins by the oxygen concentration TAD: transactivation domain; bHLH: basic helix-loop-helix; PAS: Per-ARNT-Sim homology domain. See text for further explanations of the mechanisms involved.

oxygen availability. These HIF-binding sites are called hypoxia responsive elements or for short HRE14. The activity of HIFa factors is further regulated by oxygen-dependent hydroxylation of an asparagine in their transcriptional activation domain (Figure 15.7), which prevents binding of the p300/CBP co-activator protein.

When oxygen partial pressure normalizes, the HIFa proteins are degraded and the transcriptional response to hypoxia is terminated. In von-Hippel-Lindau disease, therefore, loss of VHL leads to accumulation of HIFa proteins and constitutive activation of a transcriptional program for hypoxia response, independent of oxygen supply.

The genes that are activated by the HIFs are intriguing, when considered in the context of clear-cell carcinoma and other tumors arising in the VHL syndrome (Table 15.5).

Oxygen supply: Improved oxygen supply is achieved by several mechanisms. For instance, endothelin-1 and inducible NO synthase (iNOS) lead to increased blood flow and VEGF and PAI-1 stimulate angiogenesis (^9.4). This provides a straightforward explanation for the enhanced vascularization in tumors arising in the VHL syndrome. Iron transport proteins like transferrin and its receptor are also induced. Moreover, hypoxia also stimulates erythropoetin production in suitable

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