Hypoxia induces p53 through a pathway distinct from most DNA-damaging and stress-inducing agents.
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.
Renton
Alan
A
Ludwig Institute for Cancer Research, Imperial College of Science, Technology and Medicine at St Mary's Campus, Norfolk Place, London W2 1PG, UK.
Llanos
Susana
S
Lu
Xin
X
D000970:Antineoplastic Agents / Q000494:pharmacology; D002110:Caffeine / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D009687:Nuclear Proteins; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*
D000970:Antineoplastic Agents; D000697:Central Nervous System Stimulants; D009687:Nuclear Proteins; D018809:Proliferating Cell Nuclear Antigen; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D002110:Caffeine; D004247:DNA; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2