Hypoxia-inducible factor 1α is essential for cell cycle arrest during hypoxia

Nobuhito Goda, Heather E. Ryan, Bahram Khadivi, Wayne McNulty, Robert C. Rickert, Randall S. Johnson*

*この研究の対応する著者

研究成果: Article査読

421 被引用数 (Scopus)

抄録

A classical cellular response to hypoxia is a cessation of growth. Hypoxia-induced growth arrest differs in different cell types but is likely an essential aspect of the response to wounding and injury. An important component of the hypoxic response is the activation of the hypoxia-inducible factor I (HIF-1) transcription factor. Although this transcription factor is essential for adaptation to low oxygen levels, the mechanisms through which it influences cell cycle arrest, including the degree to which it cooperates with the tumor suppressor protein p53, remain poorly understood. To determine broadly relevant aspects of HIF-1 function in primary cell growth arrest, we examined two different primary differentiated cell types which contained a deletable allele of the oxygen-sensitive component of HIF-1, the HIF-1α gene product. The two cell types were murine embryonic fibroblasts and splenic B lymphocytes; to determine how the function of HIF-1α influenced p53, we also created double-knockout (HIF-1α null, p53 null) strains and cells. In both cell types, loss of HIF-1α abolished hypoxia-induced growth arrest and did this in a p53-independent fashion. Surprisingly, in all cases, cells lacking both p53 and HIF-1α genes have completely lost the ability to alter the cell cycle in response to hypoxia. In addition, we have found that the loss of HIF-1α causes an increased progression into S phase during hypoxia, rather than a growth arrest. We show that hypoxia causes a HIF-1α-dependent increase in the expression of the cyclin-dependent kinase inhibitors p21 and p27; we also find that hypophosphorylation of retinoblastoma protein in hypoxia is HIF-1α dependent. These data demonstrate that the transcription factor HIF-1 is a major regulator of cell cycle arrest in primary cells during hypoxia.

本文言語English
ページ(範囲)359-369
ページ数11
ジャーナルMolecular and Cellular Biology
23
1
DOI
出版ステータスPublished - 2003 1月
外部発表はい

ASJC Scopus subject areas

  • 分子生物学
  • 細胞生物学

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