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.
Rosner
Margit
M
Medical Genetics, Obstetrics and Gynecology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.
Freilinger
Angelika
A
Hanneder
Michaela
M
Fujita
Naoya
N
Lubec
Gert
G
Tsuruo
Takashi
T
Hengstschläger
Markus
M
D048948:14-3-3 Proteins / Q000378:metabolism; D000818:Animals; D002453:Cell Cycle; D002460:Cell Line; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis* / Q000502:physiology; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology
D048948:14-3-3 Proteins; C436291:CDKN1B protein, human; C493961:Cdkn1b protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27