Tristetraprolin regulates the stability of HIF-1alpha 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-1alpha expression may assist in treatment of cancer. The expression of HIF-1alpha is finely regulated via alterations in not only HIF-1alpha protein stability but also mRNA stability. However, the molecular mechanisms of regulation of HIF-1alpha 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-1alpha 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 TTP repressed the hypoxic induction of HIF-1alpha protein. Taken together, these data suggest that TTP is a modulator of HIF-1alpha 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-1alpha expression and assists with the adaptation of cancer cells to hypoxia.
Kim
Tae Woo
TW
Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, Republic of Korea.
Yim
Sujin
S
Choi
Byung Joong
BJ
Jang
Yejin
Y
Lee
Jung Ju
JJ
Sohn
Bo Hwa
BH
Yoo
Hyang-Sook
HS
Yeom
Young Il
YI
Park
Kyung Chan
KC
D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D015536:Down-Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism*; D020218:Response Elements; D051816:Tristetraprolin / Q000235:genetics / Q000378:metabolism*
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D051816:Tristetraprolin; C497552:ZFP36 protein, human