4.8 Article

An ERK-dependent pathway to Noxa expression regulates apoptosis by platinum-based chemotherapeutic drugs

期刊

ONCOGENE
卷 29, 期 49, 页码 6428-6441

出版社

NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2010.380

关键词

apoptosis; cisplatin; Noxa; BH3-only; ERK; Ras

资金

  1. Science Foundation Ireland [08/IN.1/B203]
  2. Irish Cancer Society [CRP08MAR]
  3. IRCSET

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Cisplatin is a widely used cancer chemotherapeutic that promotes DNA damage-associated apoptosis. Although platinum compounds are known to form DNA adducts and provoke DNA damage, the molecular mechanism of cisplatin-induced cell death remains unclear. In this article, we show that the BH3-only protein Noxa is strongly transcriptionally upregulated in response to cisplatin and related platinum compounds. Cisplatin-induced Noxa expression was ERK dependent, but p53 independent, and inhibition of ERK activation markedly attenuated cisplatin-induced cell death, as well as Noxa expression. Furthermore, siRNA-mediated ablation of Noxa expression also inhibited cisplatin-induced cell death and permitted clonogenic survival. These observations reveal a novel ERK-regulated route to Noxa expression that is important for the cell killing activity of platinum-based chemotherapeutic drugs. Oncogene (2010) 29, 6428-6441; doi:10.1038/onc.2010.380; published online 30 August 2010

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