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.
©2010 AACR.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Apoptosis
-
Blotting, Western
-
Cell Cycle Proteins
-
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
-
Forkhead Transcription Factors
-
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
-
Cell Cycle Proteins
-
Cyclin-Dependent Kinase Inhibitor p16
-
Cyclin-Dependent Kinase Inhibitor p21
-
FOXO4 protein, human
-
Forkhead Transcription Factors
-
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