Journal Article

Hypoxia induces p53 through a pathway distinct from most DNA-damaging and stress-inducing agents

Alan Renton, Susana Llanos and Xin Lu

in Carcinogenesis

Volume 24, issue 7, pages 1177-1182
Published in print July 2003 | ISSN: 0143-3334
Published online July 2003 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgg044
Hypoxia induces p53 through a pathway distinct from most DNA-damaging and stress-inducing agents

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The p53 tumour suppressor gene is a transcription factor that can induce cell cycle arrest and apoptosis. In response to various stress-inducing signals, p53 level increases and this is accompanied with increased activities of p53. Interestingly, the methylxanthine caffeine can abrogate the p53 accumulation induced by certain DNA-damaging agents by an unknown mechanism. In an effort to understand how different signals induce p53, human tumour cell lines were treated with combinations of various stress-inducing agents and caffeine. Caffeine inhibited the accumulation of p53 induced by leptomycin B (LMB), an inhibitor of CRM1, but not N-acetyl-leu-leu-norleucinal, a proteasome inhibitor. Furthermore, caffeine also inhibited the accumulation of p53 by a variety of stress-inducing agents in vivo, such as 5-fluorouracil, doxorubicin, mitomycin C, camptothecin and roscovitine. However, caffeine failed to affect the accumulation of p53 in hypoxia (HYP)-treated cells. These results suggested that HYP must use a distinct pathway from most DNA-damaging and stress-inducing agents to induce p53.

Keywords: ACD, actinomycin D; ALLN, N-acetyl-leu-leu-norleucinal; ATM, Ataxia telangiectasia-mutated; CAM, camptothecin; DXR, doxorubicin; HYP, hypoxia; LMB, leptomycin B; UV, ultraviolet

Journal Article.  3523 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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