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J. Biol. Chem., Vol. 279, Issue 17, 17667-17673, April 23, 2004

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Inhibition of Lens Fiber Cell Morphogenesis by Expression of a Mutant SV40 Large T Antigen That Binds CREB-binding Protein/p300 but Not pRb^*

Qin Chen, Dongcai Liang, Larry D. Fromm¶, and Paul A. Overbeek||

From the Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030 and the ^¶Center for Medical Education, Ball State University, Indiana University School of Medicine, Muncie, Indiana 47306

Simian virus (SV) 40 large T antigen can both induce tumors and inhibit cellular differentiation. It is not clear whether these cellular changes are synonymous, sequential, or distinct responses to the protein. T antigen is known to bind to p53, to the retinoblastoma (Rb) family of tumor suppressor proteins, and to other cellular proteins such as p300 family members. To test whether SV40 large T antigen inhibits cellular differentiation in vivo in the absence of cell cycle induction, we generated transgenic mice that express in the lens a mutant version of the early region of SV40. This mutant, which we term E107K, has a deletion that eliminates synthesis of small t antigen and a point mutation (E107K) that results in loss of the ability to bind to Rb family members. At embryonic day 15.5 (E15.5), the transgenic lenses show dramatic defects in lens fiber cell differentiation. The fiber cells become post-mitotic, but do not elongate properly. The cells show a dramatic reduction in expression of their - and -crystallins. Because CBP and p300 are co-activators for crystallin gene expression, we assayed for interactions between E107K and CBP/p300. Our studies demonstrate that cellular differentiation can be inhibited by SV40 large T antigen in the absence of pRb inactivation, and that interaction of large T antigen with CBP/p300 may be enhanced by a mutation that eliminates the binding to pRb.

Received for publication, October 24, 2003 , and in revised form, January 6, 2004.

^* This work was supported by National Institutes of Health Grants EY10448, EY10803, and EY11348 (to P. A. O.) and a grant from the Knights Templar Eye Foundation (Q. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: College of Optometry, University of Houston, Houston, TX 77204.

^|| To whom correspondence should be addressed: Dept. of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Tel.: 713-798-6421; Fax: 713-790-1275; E-mail: overbeek{at}bcm.tmc.edu.

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				D. R. Borger and J. A. DeCaprio Targeting of p300/CREB Binding Protein Coactivators by Simian Virus 40 Is Mediated through p53 J. Virol., May 1, 2006; 80(9): 4292 - 4303. [Abstract] [Full Text] [PDF]