Journal
CANCER RESEARCH
Volume 75, Issue 1, Pages 147-158Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-14-0036
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Funding
- NIH [P01 CA116676]
- Georgia Cancer Coalition
- Winship Cancer Institute Kennedy Seed grant
- Chinese National Natural Science Foundation [31271444, 81201726]
- Foundation for Research Cultivation and Innovation of Jinan University [21612407]
- Science and Technology Program of Guangzhou [2014J4100009]
- Guangdong Natural Science Funds for Distinguished Young Scholar
- Specialized Research Fund for the Doctoral Program of Higher Education [20124401120007]
- NATIONAL CANCER INSTITUTE [P01CA116676] Funding Source: NIH RePORTER
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Cables1 is a candidate tumor suppressor that negatively regulates cell growth by inhibiting cyclin-dependent kinases. Cables1 expression is lost frequently in human cancer but little is known about its regulation. Here, we report that Cables1 levels are controlled by a phosphorylation and 14-3-3-dependent mechanism. Mutagenic analyses identified two residues, T44 and T150, that are specifically critical for 14-3-3 binding and that serve as substrates for phosphorylation by the cell survival kinase Akt, which by binding directly to Cables1 recruits 14-3-3 to the complex. In cells, Cables1 overexpression induced apoptosis and inhibited cell growth in part by stabilizing p21 and decreasing Cdk2 kinase activity. Ectopic expression of activated Akt (AKT1) prevented Cables1-induced apoptosis. Clinically, levels of phosphorylated Cables1 and phosphorylated Akt correlated with each other in human lung cancer specimens, consistent with pathophysiologic significance. Together, our results illuminated a dynamic regulatory system through which activated Akt and 14-3-3 work directly together to neutralize a potent tumor suppressor function of Cables1. (C) 2014 AACR.
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