WNT16B is a new marker of cellular senescence that regulates p53 activity and the phosphoinositide 3-kinase/AKT pathway.
Senescence is a tumor suppression mechanism that is induced by several stimuli, including oncogenic signaling and telomere shortening, and controlled by the p53/p21(WAF1) signaling pathway. Recently, a critical role for secreted factors has emerged, suggesting that extracellular signals are necessary for the onset and maintenance of senescence. Conversely, factors secreted by senescent cells may promote tumor growth. By using expression profiling techniques, we searched for secreted factors that were overexpressed in fibroblasts undergoing replicative senescence. We identified WNT16B, a member of the WNT family of secreted proteins. We found that WNT16B is overexpressed in cells undergoing stress-induced premature senescence and oncogene-induced senescence in both MRC5 cell line and the in vivo murine model of K-Ras(V12)-induced senescence. By small interfering RNA experiments, we observed that both p53 and WNT16B are necessary for the onset of replicative senescence. WNT16B expression is required for the full transcriptional activation of p21(WAF1). Moreover, WNT16B regulates activation of the phosphoinositide 3-kinase (PI3K)/AKT pathway. Overall, we identified WNT16B as a new marker of senescence that regulates p53 activity and the PI3K/AKT pathway and is necessary for the onset of replicative senescence.
Binet
Romuald
R
Centre de Recherche Institut National de la Sante et de la Recherche Medicale/UJF-U823, Institut Albert Bonniot, La Tronche, Grenoble, France.
Ythier
Damien
D
Robles
Ana I
AI
Collado
Manuel
M
Larrieu
Delphine
D
Fonti
Claire
C
Brambilla
Elisabeth
E
Brambilla
Christian
C
Serrano
Manuel
M
Harris
Curtis C
CC
Pedeux
Rémy
R
D016922:Cellular Senescence / Q000502:physiology*; D002867:Chromones / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D014158:Transcription, Genetic; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics
D002867:Chromones; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D051153:Wnt Proteins; C493956:CDKN1A protein, human; C495901:TP53 protein, human; C417262:WNT16 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one