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

• Published in: Carcinogenesis (New York) Vol. 24; no. 7; pp. 1177 - 1182
• Main Authors: Renton, Alan, Llanos, Susana, Lu, Xin
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.07.2003; Oxford Publishing Limited (England)
• Subjects: ACD; actinomycin D; ALLN; Antineoplastic Agents - pharmacology; Ataxia telangiectasia-mutated; ATM; Biological and medical sciences; Caffeine - pharmacology; CAM; camptothecin; Cell Nucleus - metabolism; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Central Nervous System Stimulants - pharmacology; DNA - drug effects; DNA Damage; doxorubicin; DXR; Fundamental and applied biological sciences. Psychology; Humans; HYP; hypoxia; Hypoxia - metabolism; leptomycin B; LMB; Molecular and cellular biology; N-acetyl-leu-leu-norleucinal; Nuclear Proteins; Proliferating Cell Nuclear Antigen - metabolism; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-mdm2; Signal Transduction - drug effects; Stress, Physiological - metabolism; Stress, Physiological - pathology; Tumor Cells, Cultured - drug effects; Tumor Cells, Cultured - metabolism; Tumor Suppressor Protein p53 - biosynthesis; ultraviolet; Antineoplastic agent; Signal transduction; Oxygen; TP53 Gene; DNA; Hypoxia; Lesion; Gene expression; Mechanism of action; Comparative study; Stress; Tumor suppressor gene
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgg044

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.