Halting HIF

Science's STKE  04 Dec 2001:
Vol. 2001, Issue 111, pp. tw444
DOI: 10.1126/stke.2001.111.tw444

Hypoxia-inducible transcription factors (HIFs) alter gene expression in response to low oxygen conditions. Makino et al. have identified a protein called IPAS [for inhibitory PAS (Per, Arnt, Sim)-domain protein] that is structurally similar to HIF. However, overexpression of IPAS inhibited HIF-1α from inducing the expression of genes such as vascular endothelial growth factor (VEGF) under hypoxic conditions. A fusion protein of glutathione S-transferase with IPAS and in vitro-translated HIF-1α were precipitated together in vitro, suggesting that negative regulation might involve direct interaction. IPAS was highly expressed in the corneal epithelium, and when inhibited by expression of an antisense vector, allowed hypoxia-induced activation of VEGF expression and subsequent blood vessel growth. The authors propose that for tissues such as the cornea, which are normally subjected to hypoxia, IPAS serves as an anti-angiogenic mechanism to suppress HIF action.

Y. Makino, R. Cao, K. Svensson, G. Bertilsson, M. Asman, H. Tanaka, Y. Cao, A. Berkenstam, L. Poellinger, Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression. Nature 414, 550-554 (2001). [Online Journal]