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M405528200v1
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Papers In Press, published online ahead of print September 8, 2004
J. Biol. Chem, 10.1074/jbc.M405528200
Submitted on May 18, 2004
Revised on September 8, 2004
Accepted on September 8, 2004

Tuberin binds p27 and negatively regulates its interaction with the SCF component Skp2

Margit Rosner and Markus Hengstschläger

Obstetrics and Gynecology, Prenatal Diagnosis and Therapy, Vienna 1090

Corresponding Author: markus.hengstschlaeger{at}akh-wien.ac.at

TSC1, encoding hamartin, and TSC2, encoding tuberin are tumor suppressor genes responsible for the autosomal dominantly inherited disease tuberous sclerosis. They have been demonstrated to negatively regulate cell cycle progression, the activity of cdk2 and the degradation of the cyclin-dependent kinase inhibitor p27. So far, the underlying molecular mechanism remains elusive. Here, we show that tuberin binds to p27. Whereas tuberin also binds p27 in TSC1-negative cells, hamartin does not bind p27 without tuberin. p27 protein levels are regulated through ubiquitin-dependent degradation. Skp2 is the F-box protein, which together with other proteins forms an SCF-type E3 ubiquitin ligase complex, whose task is to target p27 for degradation by the proteasome. We found that neither tuberin nor hamartin are in a complex with Skp2. Tuberin does not affect Skp2 protein levels, and the SCFSkp2 ubiquitin ligase does not regulate tuberin stability. But binding of tuberin to p27 sequesters p27 from Skp2 accompanied by an upregulation of p27 interaction with cdk2. Skp2-induced p27 degradation and cell cycle progression is abolished by tuberin´s protective binding to p27. This, the first description of the direct interaction of a tumor suppressor protein with p27, provides a molecular explanation for the effects of TSC genes on the cell cycle and demonstrates a new aspect of the SCFSkp2 mediated regulation of p27 stability.


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