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Molecular and Cellular Biology, May 2001, p. 3302-3313, Vol. 21, No. 10
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.10.3302-3313.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Mechanism for Mutational Inactivation of the Tumor Suppressor Smad2

Celine Prunier,1 Nathalie Ferrand,1 Bertrand Frottier,2 Marcia Pessah,1 and Azeddine Atfi1,*

INSERM U 482, Hôpital Saint-Antoine, 75571 Paris Cedex 12,1 and Laboratoire de Minéralogie-Cristallographie, Université Pierre et Marie Curie, 75252 Paris Cedex 05,2 France

Received 12 June 2000/Returned for modification 5 September 2000/Accepted 21 February 2001

Transforming growth factor beta  (TGF-beta ) is a potent natural antiproliferative agent that plays an important role in suppressing tumorigenicity. In numerous tumors, loss of TGF-beta responsiveness is associated with inactivating mutations that can occur in components of this signaling pathway, such as the tumor suppressor Smad2. Although a general framework for how Smads transduce TGF-beta signals has been proposed, the physiological relevance of alterations of Smad2 functions in promoting tumorigenesis is still unknown. Here, we show that expression of Smad2.P445H, a tumor-derived mutation of Smad2 found in human cancer, suppresses the ability of the Smads to mediate TGF-beta -induced growth arrest and transcriptional responses. Smad2.P445H is phosphorylated by the activated TGF-beta receptor at the carboxy-terminal serine residues and associates with Smad3 and Smad4 but is unable to dissociate from the receptor. Upon ligand-induced phosphorylation, Smad2.P445H interacts stably with wild-type Smad2, thereby blocking TGF-beta -induced nuclear accumulation of wild-type Smad2 and Smad2-dependent transcription. The ability of the Smad2.P445H to block the nuclear accumulation of wild-type Smad2 protein reveals a new mechanism for loss of sensitivity to the growth-inhibitory functions of TGF-beta in tumor development.

* Corresponding author. Mailing address: INSERM U 482, Hôpital Saint-Antoine, 184 Rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France. Phone: (33, 1) 49 28 46 11. Fax: (33, 1) 40 19 90 62. E-mail: atfi{at}adr.st-antoine.inserm.fr.

Molecular and Cellular Biology, May 2001, p. 3302-3313, Vol. 21, No. 10
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.10.3302-3313.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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