Question

Question 36 6 p A mutation that changes the prollnes normally hydroxylated In HIF1a to alanines dramatically increases VEGF expression in the absence of hypoxia. Provide a likely reason for this changed VEGF expression, and explain your reasoning.

Answer 1

During O2 rich conditions (normoxia), the proline residues of Hif1a is hydroxylated by the enzyme prolyl hydroxylase. This enzyme is O2 dependent enzyme. Besides proline hydroxylation, asparagine is also hydroxylated by asparaginyl hydroxylase. Hydroxylation of Hif1a leads to ubiqutination of Hif1a protein by VHL E3 ubiquitine ligase. Ubiqutination of Hif1a leads its degradation by proteosome machionary.

But in hypoxia conditions (O2 depleted), the hydroxylation is not occurred. Thus, the proteosome mediated degradation of Hif1a is not possible and Hif1a form a heterodimer with Hif1b. This heterodimer migrates to the nucleus and bound to the HRE (hypoxia responsive elements) containing genes. VEGF is one of the target of Hif1a.

Thus, a mutation of proline to alanine will not allow the prolyl hydroxylase to hydroxylate alanine. Thus, no hydroxylation means no degradation of Hif1a. So, Hif1a will form heterodimer and help in the expression of VEGF in high amount even in normoxia conditions.