p27Kip1 localization depends on the tumor suppressor protein tuberin.
p27(Kip1) plays an important role in cell cycle regulation by inhibiting cyclin-CDK complex activity in the nucleus. p27(Kip1) 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 by 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.
Mesh Terms:
14-3-3 Proteins, Animals, Cell Cycle, Cell Line, Cyclin-Dependent Kinase Inhibitor p27, Gene Expression Regulation, HeLa Cells, Humans, Intracellular Signaling Peptides and Proteins, Mice, Mice, Transgenic, NIH 3T3 Cells, Phosphorylation, Tumor Suppressor Proteins
14-3-3 Proteins, Animals, Cell Cycle, Cell Line, Cyclin-Dependent Kinase Inhibitor p27, Gene Expression Regulation, HeLa Cells, Humans, Intracellular Signaling Peptides and Proteins, Mice, Mice, Transgenic, NIH 3T3 Cells, Phosphorylation, Tumor Suppressor Proteins
Hum. Mol. Genet.
Date: Jul. 01, 2007
PubMed ID: 17470459
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