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Molecular and Cellular Biology, April 2005, p. 3338-3347, Vol. 25, No. 8
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.8.3338-3347.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Transforming Growth Factor ß Facilitates ß-TrCP-Mediated Degradation of Cdc25A in a Smad3-Dependent Manner

Dipankar Ray,¹ Yasuhisa Terao,¹ Dipali Nimbalkar,¹ Li-Hao Chu,¹ Maddalena Donzelli,² Tateki Tsutsui,^1, Xianghong Zou,¹ Asish K. Ghosh,^3, John Varga,^3, Giulio F. Draetta,² and Hiroaki Kiyokawa^1*

Department of Biochemistry and Molecular Genetics,¹ Section of Rheumatology, University of Illinois College of Medicine, Chicago, Illinois,³ European Institute of Oncology, Milan, Italy²

Received 26 August 2004/ Returned for modification 21 September 2004/ Accepted 3 January 2005

Ubiquitin-dependent degradation of Cdc25A is a major mechanism for damage-induced S-phase checkpoint. Two ubiquitin ligases, the Skp1-cullin-ß-TrCP (SCF^ß-TrCP) complex and the anaphase-promoting complex (APC^Cdh1), are involved in Cdc25A degradation. Here we demonstrate that the transforming growth factor ß (TGF-ß)-Smad3 pathway promotes SCF^ß-TrCP-mediated Cdc25A ubiquitination. Cells treated with TGF-ß, as well as cells transfected with Smad3 or a constitutively active type I TGF-ß receptor, exhibit increased ubiquitination and markedly shortened half-lives of Cdc25A. Furthermore, Cdc25A is stabilized in cells transfected with Smad3 small interfering RNA (siRNA) and cells from Smad3-null mice. TGF-ß-induced ubiquitination is associated with Cdc25A phosphorylation at the ß-TrCP docking site (DS⁸²G motif) and physical association of Cdc25A with Smad3 and ß-TrCP. Cdc25A mutant proteins deficient in DS⁸²G phosphorylation are resistant to TGF-ß-Smad3-induced degradation, whereas a Cdc25A mutant protein defective in APC^Cdh1 recognition undergoes efficient degradation. Smad3 siRNA inhibits ß-TrCP-Cdc25A interaction and Cdc25A degradation in response to TGF-ß. ß-TrCP2 siRNA also inhibits Smad3-induced Cdc25A degradation. In contrast, Cdh1 siRNA had no effect on Cdc25A down-regulation by Smad3. These data suggest that Smad3 plays a key role in the regulation of Cdc25A ubiquitination by SCF^ß-TrCP and that Cdc25A stabilization observed in various cancers could be associated with defects in the TGF-ß-Smad3 pathway.

Present address: Department of Obstetrics and Gynecology, Osaka University Medical School, Osaka 565-0871, Japan.

Present address: Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.

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