Human Molecular Genetics Advance Access published online on April 30, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm103
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p27Kip1localization depends on the tumor suppressor protein tuberin
1 Medical Genetics, Obstetrics and Gynecology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria 2 Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032, Japan 3 Department of Pediatrics, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria
* To whom correspondence should be addressed: Markus Hengstschläger, PhD, Prof Medical Genetics, Obstetrics and Gynecology, Medical University of Vienna Währinger Gürtel 18-20, 1090 Vienna, Austria; Tel: +43/1/40400/7847, FAX: +43/1/40400/7848, E-mail: markus.hengstschlaeger{at}meduniwien.ac.at
Received February 2, 2007; Revised April 12, 2007; Accepted April 12, 2007
p27Kip1 plays an important role in cell cycle regulation via inhibiting cyclin-CDK complex activity in the nucleus. p27Kip1 is regulated by its concentration as well as by its subcellular localization.
Tuberin, encoded by the tuberous sclerosis tumor suppressor gene TSC2, is a potent negative cell cycle regulator.
We show herein, that tuberin induces nuclear p27 localization via inhibiting its 14-3-3-mediated cytoplasmic retention. Tuberin interferes with 14-3-3's counteracting effects on p27-mediated cell cycle arrest. Akt-mediated phosphorylation of p27, but not of tuberin, negatively regulates tuberin's potential to trigger p27 nuclear localization. In G0 cells tuberin binds p27 triggering downregulation of p27's binding to 14-3-3 and of its cytoplasmic retention. At transition to S phase p27 is phosphorylated by Akt, tuberin/p27 complex levels are downregulated, and binding of p27 to 14-3-3 increases triggering cytoplasmic retention of p27. These findings demonstrate p27 localization during the mammalian cell cycle to be under the control of the tumor suppressor tuberin.
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