Activation of forkhead box O transcription factors by oncogenic BRAF promotes p21cip1-dependent senescence

de Keizer, Peter L.J., Packer, Leisl M., Szypowska, Anna A., Riedl-Polderman, Paulien E., van den Broek, Niel J.F., de Bruin, Alain, Dansen, Tobias B., Marais, Richard, Brenkman, Arjan B., & Burgering, Boudewijn M.T. (2010) Activation of forkhead box O transcription factors by oncogenic BRAF promotes p21cip1-dependent senescence. Cancer Research, 70(21), pp. 8526-8536.

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Abstract

Oncogene-induced senescence (OIS) is a potent tumor-suppressive mechanism that is thought to come at the cost of aging. The Forkhead box O (FOXO) transcription factors are regulators of life span and tumor suppression. However, whether and how FOXOs function in OIS have been unclear. Here, we show a role for FOXO4 in mediating senescence by the human BRAFV600E oncogene, which arises commonly in melanoma. BRAFV600E signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-Jun NH 2 terminal kinase-mediated activation of FOXO4 via its phosphorylation on Thr223, Ser226, Thr447, and Thr451. BRAFV600E-induced FOXO4 phosphorylation resulted in p21cip1-mediated cell senescence independent of p16 ink4a or p27kip1. Importantly, melanocyte-specific activation of BRAFV600E in vivo resulted in the formation of skin nevi expressing Thr223/Ser226-phosphorylated FOXO4 and elevated p21cip1. Together, these findings support a model in which FOXOs mediate a trade-off between cancer and aging.

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ID Code: 76309
Item Type: Journal Article
Refereed: Yes
Additional Information: Articles free to read on journal website after 12 months
Keywords: B Raf kinase; cyclin dependent kinase inhibitor 1; mitogen activated protein kinase kinase; protein p16; protein p27; reactive oxygen metabolite; serine; stress activated protein kinase; threonine; transcription factor FOXO; article; cancer inhibition; ce
DOI: 10.1158/0008-5472.CAN-10-1563
ISSN: 1538-7445
Subjects: Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > MEDICAL BIOCHEMISTRY AND METABOLOMICS (110100)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200)
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Deposited On: 23 Sep 2014 23:33
Last Modified: 28 Jan 2015 00:52

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