WNT16B Is a New Marker of Cellular Senescence That Regulates p53 Activity and the Phosphoinositide 3-Kinase/AKT Pathway

Abstract

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 KRas 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. [Cancer Res 2009;69(24):9183-91]

MicroRNA-374b Suppresses Proliferation and Promotes Apoptosis in T-cell Lymphoblastic Lymphoma by Repressing AKT1 and Wnt-16

“…Wnt16b was initially described as an oncogene that activated b-catenin in pre-B acute lymphoblastoid leukemia or enhanced the survival of cancer cells with or without cytotoxic therapy via a b-catenin-independent noncanonical WNT transduction pathway (37,38). Furthermore, Binet and colleagues reported Wnt16b was identified as a new marker of senescence and over-expression of Wnt16b activated the PI3K/AKT pathway (26). Consistent with previous reports, overexpression of Wnt16b in our SUP-T1-374b cells partly rescued the levels of phospho-AKT, which was suppressed by miR374b ( Supplementary Fig.…”

“…Given that both Wnt16 and AKT1 play crucial roles in the AKT signaling pathway (26,27), the roles of miR-374b in the activation of AKT were investigated. Interestingly, the expression of phosphorylated AKT and total AKT was dramatically decreased by the restoration of miR-374b in Jurkat and SUP-T1 cells.…”

A Decline in Wnt3a Signaling is Necessary for Mesenchymal Stem Cells to Proceed to Replicative Senescence

“…S4). Indeed, senescent MSCs express the others of secreted Wnts and signaling mediators that affect self-renewal and differentiation [13,29]. It has been reported that elevated Wnt5a expression in aged hematopoietic stem cells causes a shift from canonical to noncanonical Wnt signaling, thereby resulting in stem cell aging [30].…”

Wnt Signaling and Aging-Related Heart Disorders

“…8,19 In addition to these classic markers of cellular senescence, Binet et al recently reported that Wnt16B is a marker of senescent cells. 20 Wnt16B is overexpressed in cells undergoing replicative or stress-induced senescence in vitro and those in K-Ras-induced adenomas in vivo, and forced expression of Wnt16B accelerates, whereas knockdown of Wnt16B attenuates, the onset of cellular senescence. However, because these authors failed to detect the activation of Wnt/␤-catenin signaling by Wnt16B, the link between Wnt signaling and cellular senescence is not evident in this context.…”