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Mol Cell Biol, March 1998, p. 1408-1415, Vol. 18, No. 3
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

The J Domain of Simian Virus 40 Large T Antigen Is Required To Functionally Inactivate RB Family Proteins

Juan Zalvide,dagger Hilde Stubdal,Dagger and James A. DeCaprio*

Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115

Received 23 September 1997/Returned for modification 29 October 1997/Accepted 19 December 1997

Transformation by simian virus 40 large T antigen (TAg) is dependent on the inactivation of cellular tumor suppressors. Transformation minimally requires the following three domains: (i) a C-terminal domain that mediates binding to p53; (ii) the LXCXE domain (residues 103 to 107), necessary for binding to the retinoblastoma tumor suppressor protein, pRB, and the related p107 and p130; and (iii) an N-terminal domain that is homologous to the J domain of DnaJ molecular chaperone proteins. We have previously demonstrated that the N-terminal J domain of TAg affects the RB-related proteins by perturbing the phosphorylation status of p107 and p130 and promoting the degradation of p130 and that this domain is required for transformation of cells that express either p107 or p130. In this work, we demonstrate that the J domain of TAg is required to inactivate the ability of each member of the pRB family to induce a G1 arrest in Saos-2 cells. Furthermore, the J domain is required to override the repression of E2F activity mediated by p130 and pRB and to disrupt p130-E2F DNA binding complexes. These results imply that while the LXCXE domain serves as a binding site for the RB-related proteins, the J domain plays an important role in inactivating their function.

* Corresponding author. Mailing address: Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney St., Boston, MA 02115. Phone: (617) 632-3825. Fax: (617) 632-4381. E-mail: james_decaprio{at}dfci.harvard.edu.

dagger Present address: Department of Biochemistry, University of Santiago de Compostela, Santiago de Compostela, La Coruna 15705, Spain.

Dagger Present address: Millennium Pharmaceuticals, Cambridge, MA 02139.




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