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Inhibition of crystallin expression and induction of apoptosis by lens-specific E1A expression in transgenic mice

Oncogene volume 21, pages 1028–1037 (2002)Cite this article

Abstract

Previous studies have shown that the adenovirus E1A oncoprotein can bind to and inactivate the retinoblastoma tumor suppressor protein (pRb) and the transcriptional coactivators CBP/p300. In this study, wild-type E1A12S or two deletion mutants (delN, which binds pRb but not CBP/p300; delCR2, which binds to CBP/p300 but not pRb) were linked to the lens-specific αA-crystallin promoter, and used to generate transgenic mice. Lens fiber cells expressing E1A12S or delCR2, both of which bind to CBP/p300, failed to upregulate β-crystallin and γ-crystallin expression. In contrast, lens fiber cells expressing delN showed significant expression of β- and γ-crystallins. Lens fiber cells expressing delN showed cell cycle entry, marked apoptosis, and evidence for p53 activation, while cells expressing either 12S or delCR2 showed limited apoptosis and no evidence for upregulation of the p53-inducible gene p21. Our results suggest that the transcriptional coactivators CBP and/or p300 are required for the dramatic increases in crystallin expression that accompany terminal differentiation in the lens, and also for activation of p53 in response to inactivation of pRb in the lens.

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Acknowledgements

We thank Greg Barsh, Brian Ring and Michael Schneider for helpful comments on the manuscript; Gaby Schuster for generating the transgenic mice; Long Vien, Barbara Harris and Rachel Charbonneau for excellent technical assistance. This research was supported by NRSA fellowship EY-06708 (JD Ash), NIH grants EY-10448, EY-10803, EY-11348 (PA Overbeek); and a grant from the National Cancer Institute of Canada (P Branton).

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Author notes

  1. John D Ash

    Present address: Department of Ophthalmology, Dean A. McGee Eye Institute, 608 Stanton L. Young Blvd., Oklahoma City, 73104, OK, USA

Authors and Affiliations

  1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, 77030, Texas, TX, USA

    Qin Chen, John D Ash & Paul A Overbeek

  2. Department of Biochemistry, McGill University, Montreal, Quebec, H3G1Y6, Canada

    Phil Branton

  3. Skirball Institute, New York University Medical School, New York, 10012, NY, USA

    Larry Fromm

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  1. Qin Chen
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  2. John D Ash
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  5. Paul A Overbeek
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Corresponding author

Correspondence to Paul A Overbeek.

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Chen, Q., Ash, J., Branton, P. et al. Inhibition of crystallin expression and induction of apoptosis by lens-specific E1A expression in transgenic mice. Oncogene 21, 1028–1037 (2002). https://doi.org/10.1038/sj.onc.1205050

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