Anoxic Fibroblasts Activate a Replication Checkpoint that Is Bypassed by E1a

Lawrence B. Gardner, Feng Li, Xuejie Yang, Chi V. Dang

Research output: Contribution to journalArticle

Abstract

Little is known about cell cycle regulation in hypoxic cells, despite its significance. We utilized an experimentally tractable model to study the proliferative responses of rat fibroblasts when rendered hypoxic (0.5% oxygen) or anoxic (1 arrest, whereas anoxic cells also demonstrated S-phase arrest due to suppression of DNA initiation. Upon reoxygenation, only those cells arrested in G1 were able to resume proliferation. The oncoprotein E1a induced p53-independent apoptosis in anoxic cells, which when suppressed by Bcl-2 permitted proliferation despite anoxia. E1a expression led to marked increases in the transcription factor E2F, and overexpression of E2F-1 allowed proliferation in hypoxic cells, although it had minimal effect on the anoxic suppression of DNA initiation. We thus demonstrate two distinct cell cycle responses to low oxygen and suggest that alterations that lead to increased E2F can overcome hypoxic G1 arrest but that additional alterations, promoted by E1a expression, are necessary for neoplastic cells to proliferate despite anoxia.

Original languageEnglish (US)
Pages (from-to)9032-9045
Number of pages14
JournalMolecular and Cellular Biology
Volume23
Issue number24
DOIs
StatePublished - Dec 2003

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Fibroblasts
Cell Cycle
E2F Transcription Factors
Oxygen
Oncogene Proteins
DNA
S Phase
Apoptosis
Hypoxia

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Anoxic Fibroblasts Activate a Replication Checkpoint that Is Bypassed by E1a. / Gardner, Lawrence B.; Li, Feng; Yang, Xuejie; Dang, Chi V.

In: Molecular and Cellular Biology, Vol. 23, No. 24, 12.2003, p. 9032-9045.

Research output: Contribution to journalArticle

Gardner, Lawrence B. ; Li, Feng ; Yang, Xuejie ; Dang, Chi V. / Anoxic Fibroblasts Activate a Replication Checkpoint that Is Bypassed by E1a. In: Molecular and Cellular Biology. 2003 ; Vol. 23, No. 24. pp. 9032-9045.
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