Regulation of HIF-1a protein synthesis
MNK phosphorylates eIF-4E and stimulates its activity directly.
Active eIF-4E increases the rate of HIF1A-mRNA translation into HIF1A protein.
HIF-1B (ARNT) is constitutively expressed and itsmRNA and protein are maintained at constant levels regardless of oxygen availability
HIF-1A protein has a short half-life (t1/2 = 5 min) and is highly regulated by oxygen
The transcription and synthesis of HIF-1B are constitutive and seem not to be affected by oxygen.
In normoxia, the HIF-1A proteins are rapidly degraded, resulting in essentially no detectable HIF-1A protein.
During hypoxia, HIF-1A becomes stabilized and translocates from the cytoplasm to the nucleus, where it dimerizes with HIF-1B and the HIF complex formed becomes transcriptionally active
The activated HIF complex then associates with HREs in the regulatory regions of target genes and binds the transcriptional coactivators to induce gene expression.
Tight regulation of the stability and subsequent transactivational function of HIF-1A is chiefly controlled by its post-translation modifications, such as hydroxylation, ubiquitination, acetylation, and phosphorylation
The modification of HIF-1A occurs within several domains.
In normoxia, hydroxylation of 2 proline residues and acetylation of a lysine residue in its ODDD promote interaction of HIF-1A with the von Hippel-Lindau (pVHL) ubiquitin E3 ligase complex (Srinivas et al., 1999; Masson et al., 2001).
pVHL complex tags HIF-1A with ubiquitin and thereby marks it for degradation by the 26S proteasome.
In addition, hydroxylation of an asparagine residue in the C-TAD inhibits the association of HIF-1A with CBP/p300 and thus inhibits its transcriptional activity (Lando et al., 2002a).