Cyclin dependent kinase inhibitor p27Kip1 is upregulated by hypoxia via an ARNT dependent pathway

Gang Wang, Richard Reisdorph, Robert E. Clark, Robin Miskimins, Ronald Lindahl, W. Keith Miskimins

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Expression of cyclin dependent kinase (Cdk) inhibitor p27Kip1, which blocks cell cycle progression from G1 to S phase, can be regulated via multiple mechanisms including transcription, protein degradation, and translation. Recently, it was shown that p27Kip1 plays an important role in the cellular response to hypoxia. However, the mechanisms involved in the hypoxia-induced regulation of p27Kip1 expression are still not clear. In this study, we compare the expression of p27Kip1 in two related murine hepatoma cell lines, Hepa-1 and c4. Hepa-1 produces functional aryl hydrocarbon receptor nuclear translocator (ARNT). c4 cells are derived from Hepa-1, but are ARNT deficient. Interestingly, we observed cell line-dependent effects of hypoxia on the expression of p27Kip1. The level of p27Kip1 protein in Hepa-1 cells is enhanced by hypoxia, but is reduced by hypoxia in c4 cells. Further investigation demonstrated that hypoxia-induced, ARNT-mediated, transactivation of the p27Kip1 gene in Hepa-1 cells is responsible for the increase in p27Kip1 protein. Once c4 cells were stably transfected with the wild type ARNT gene, a hypoxia-induced increase in p27Kip1 mRNA was observed and reduction of p27Kip1 protein caused by hypoxia was blocked. Hence, our data indicate that ARNT is involved in transcriptional upregulation of the p27 Kip1 gene under hypoxic conditions.

Original languageEnglish (US)
Pages (from-to)548-560
Number of pages13
JournalJournal of Cellular Biochemistry
Volume90
Issue number3
DOIs
StatePublished - Oct 15 2003

Fingerprint

Aryl Hydrocarbon Receptor Nuclear Translocator
Cyclin-Dependent Kinases
Cyclin-Dependent Kinase Inhibitor p27
Genes
Cells
Transcription
Cell Line
Hypoxia
Protein Biosynthesis
Degradation
S Phase
Messenger RNA
Transcriptional Activation
Proteolysis
Hepatocellular Carcinoma
Cell Cycle
Up-Regulation
Proteins

Keywords

  • ARNT
  • Cell cyle
  • HIF
  • Hypoxia
  • P27

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Cyclin dependent kinase inhibitor p27Kip1 is upregulated by hypoxia via an ARNT dependent pathway. / Wang, Gang; Reisdorph, Richard; Clark, Robert E.; Miskimins, Robin; Lindahl, Ronald; Miskimins, W. Keith.

In: Journal of Cellular Biochemistry, Vol. 90, No. 3, 15.10.2003, p. 548-560.

Research output: Contribution to journalArticle

Wang, Gang ; Reisdorph, Richard ; Clark, Robert E. ; Miskimins, Robin ; Lindahl, Ronald ; Miskimins, W. Keith. / Cyclin dependent kinase inhibitor p27Kip1 is upregulated by hypoxia via an ARNT dependent pathway. In: Journal of Cellular Biochemistry. 2003 ; Vol. 90, No. 3. pp. 548-560.
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