Tristetraprolin regulates the stability of HIF-1 alpha mRNA during prolonged hypoxia

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor involved in the cancer cell adaptation to hypoxia, a leading Cause of tumor malignancy. Thus, control of HIF-1 alpha expression may assist in treatment of cancer The expression of HIF-1 alpha is finely regulated via alterations in not only HIF-1 alpha. protein stability but also mRNA stability However, the molecular mechanisms of regulation of HIF-1 alpha. mRNA stability have not yet been fully elucidated Here, we show that tristetraprolin (TTP) protein, of which the mRNA expression level is downregulated in most of hepatocellular carcinoma tissues. bound directly to the 3'- UTR of HIF-1 alpha mRNA containing eight putative TTP-binding motifs, AU-rich elements (AUUUA). to downregulate stability. Furthermore. TTP expression was induced in hypoxic cells, and overexpression of 1713 repressed the hypoxic induction of HIF-1 alpha protein Taken together. these data Suggest that TTP is a modulator of HIF-1 alpha expression during hypoxia and may play a physiological role in regulation between cellular adaptation and apoptosis in prolonged hypoxia In addition, cancer cells may benefit from the downregulation of TTP. which subsequently increases HIF-1 alpha expression and assists with the adaptation of cancer cells to hypoxia. (C) 2009 Elsevier Inc All rights reserved