Article
- The EMBO Journal (2005) 24, 170 - 179
- doi:10.1038/sj.emboj.7600502
Published online: 16 December 2004
Subject Categories:
5-Lipoxygenase regulates senescence-like growth arrest by promoting ROS-dependent p53 activation
Alfonso Catalano1,2, Sabrina Rodilossi1, Paola Caprari1,3, Vincenzo Coppola3 and Antonio Procopio1,2
- Department of Molecular Pathology and Innovative Therapies, Polytechnic University of Marche, Ancona, Italy
- Laboratory of Cytology, Italian National Research Centers on Aging, Ancona, Italy
- Neural Development Group, Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD, USA
Correspondence to:
Alfonso Catalano, Dipartimento di Patologia Molecolare e Terapie Innovative, Università Politecnica delle Marche, Via Ranieri, 60131, Ancona, Italy. Tel.: +39 07 12 20 46 23; Fax: +39 07 12 20 46 18; E-mail: catgfp@yahoo.it
Received 21 July 2004; Accepted 11 November 2004
Abstract
5-Lipoxygenase (5LO) is involved in the production of leukotrienes and reactive oxygen species (ROS) from arachidonic acid. Its strong activation has been associated with several diseases like cancer and neurodegeneration. Here we show that 5LO activity increases during senescence-like growth arrest induced by oncogenic ras or culture history in both human and mouse embryo fibroblasts. Overexpression of 5LO promotes senescence-like growth arrest via a p53/p21-dependent pathway, and this occurs independently of telomerase activity. 5LO stabilizes p53 through phosphorylation at Ser15 and increases expression of the p53-transcriptional target p21. This is achieved by regulating ROS production. Indeed, ROS are increased in 5LO-arrested cells. Antioxidants and a low oxygen environment prevent 5LO-induced growth arrest. Finally, 5LO inhibition reduces the growth arrest induced by oncogenic ras or culture history and these effects are neutralized by the addition of exogenous ROS. These data link the 5LO pathway to oxidative crises of primary fibroblast and suggest that the ability of 5LO to induce senescence-like growth arrest may be important in the pathogenesis of 5LO-associated disorders.
Keywords:
- 5-lipoxygenase,
- oncogenic ras,
- p53,
- reactive oxygen species,
- senescence
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