Activation of Forkhead Box O Transcription Factors by Oncogenic BRAF Promotes p21cip1-dependent Senescence

Cancer Res. 2010 Nov 1;70(21):8526-36. doi: 10.1158/0008-5472.CAN-10-1563. Epub 2010 Oct 19.

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 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 independent of p16(ink4a) or p27(kip1). Importantly, melanocyte-specific activation of BRAF(V600E) in vivo resulted in the formation of skin nevi expressing Thr(223)/Ser(226)-phosphorylated FOXO4 and elevated p21(cip1). Together, these findings support a model in which FOXOs mediate a trade-off between cancer and aging.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Blotting, Western
  • Cell Proliferation
  • Cellular Senescence*
  • Colony-Forming Units Assay
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / antagonists & inhibitors
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • Cyclin-Dependent Kinase Inhibitor p27
  • Humans
  • In Situ Nick-End Labeling
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • JNK Mitogen-Activated Protein Kinases / genetics
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Melanocytes / metabolism*
  • Melanocytes / pathology
  • Melanoma / genetics
  • Melanoma / metabolism
  • Melanoma / pathology*
  • Mice
  • Phosphorylation
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins B-raf / metabolism*
  • RNA, Messenger / genetics
  • RNA, Small Interfering / pharmacology
  • Reactive Oxygen Species / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Skin Neoplasms / genetics
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology*
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Xenograft Model Antitumor Assays

Substances

  • CDKN1A protein, human
  • CDKN1B protein, human
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p21
  • FOXO4 protein, human
  • Intracellular Signaling Peptides and Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Transcription Factors
  • Cyclin-Dependent Kinase Inhibitor p27
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • JNK Mitogen-Activated Protein Kinases