biostudies-literaturede Keizer PLCancer Research UK8526-36https://www.ebi.ac.uk/biostudies/studies/S-EPMC2989643biostudies-literatureUnknown70(21)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 BRAF(V600E) oncogene, which arises commonly in melanoma. BRAF(V600E) 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 Thr(223), Ser(226), Thr(447), and Thr(451). BRAF(V600E)-induced FOXO4 phosphorylation resulted in p21(cip1)-mediated cell senescence independCancer researchActivation of forkhead box O transcription factors by oncogenic BRAF promotes p21cip1-dependent senescence.PMC2989643A10433Ref C107/A10433van den Broek NJde Keizer PLBrenkman ABde Bruin AMarais RBurgering BMRiedl-Polderman PEPacker LMSzypowska AADansen TBfalseActivation of forkhead box O transcription factors by oncogenic BRAF promotes p21cip1-dependent senescence.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 BRAF(V600E) oncogene, which arises commonly in melanoma. BRAF(V600E) 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 Thr(223), Ser(226), Thr(447), and Thr(451). BRAF(V600E)-induced FOXO4 phosphorylation resulted in p21(cip1)-mediated cell senescence independ2010-01-01T00:00:00Z2010 Nov2025-04-18T14:38:04.176Z2019-03-27T00:36:53ZS-EPMC29896432095947510.1158/0008-5472.can-10-156310.1158/0008-5472.CAN-10-1563