The ocular lens provides an ideal system to study cell cycle regulation during terminal differentiation. The lens is composed of two cell types: the epithelial cells, which are capable of cellular proliferation, and the fiber cells, which are post-mitotic. I hypothesize that the differentiation of epithelial cells into fiber cells will cause alterations in activity of the genes that regulate the cell cycle. In order to help test this hypothesis, the alphaA-crystallin promoter will be used to direct lens-specific alterations in gene expression in transgenic mice. Transgenic and non-transgenic mice will be used to study two general classes of genes that are likely to be critical for cell cycle control during differentiation: tumor suppressors and cyclin-dependent kinases.
The Specific Aims of this grant application are: l) to assess the role of the retinoblastoma (rb) protein in cell cycle control and terminal differentiation of lens fiber cells; 2) to assess the role of p53 in the induction of lens tumors by SV4O large T antigen; 3) to assay for changes in cyclin dependent kinases that accompany fiber cell differentiation; 4) to characterize the cell death that is induced by rb inactivation in fiber cells; and 5) to genetically reverse lens tumorigenesis induced by full-length T antigen. Our preliminary experiments have shown that expression of viral proteins that bind to rb and/or p53 can induce lens cell tumorigenesis or programmed cell death. Therefore, the cell cycle can be altered in lens cells with fascinating and unexpected consequences. The proposed studies should provide insights into cell cycle regulation in vivo, not only for the lens, but for other cells undergoing terminal differentiation or neoplastic transformation.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY010803-04
Application #
2518764
Study Section
Visual Sciences A Study Section (VISA)
Project Start
1994-09-01
Project End
1999-08-31
Budget Start
1997-09-01
Budget End
1998-08-31
Support Year
4
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Chen, Qin; Liang, Dongcai; Overbeek, Paul A (2008) Overexpression of E2F5/p130, but not E2F5 alone, can inhibit E2F-induced cell cycle entry in transgenic mice. Mol Vis 14:602-14
Govindarajan, Venkatesh; Overbeek, Paul A (2006) FGF9 can induce endochondral ossification in cranial mesenchyme. BMC Dev Biol 6:7
Govindarajan, Venkatesh; Harrison, Wilbur R; Xiao, Ningna et al. (2005) Intracorneal positioning of the lens in Pax6-GAL4/VP16 transgenic mice. Mol Vis 11:876-86
Graham, Dianca R; Overbeek, Paul A; Ash, John D (2005) Leukemia inhibitory factor blocks expression of Crx and Nrl transcription factors to inhibit photoreceptor differentiation. Invest Ophthalmol Vis Sci 46:2601-10
Zhao, Haotian; Yang, Ying; Rizo, Christian M et al. (2004) Insertion of a Pax6 consensus binding site into the alphaA-crystallin promoter acts as a lens epithelial cell enhancer in transgenic mice. Invest Ophthalmol Vis Sci 45:1930-9
Chen, Qin; Liang, Dongcai; Yang, Tao et al. (2004) Distinct capacities of individual E2Fs to induce cell cycle re-entry in postmitotic lens fiber cells of transgenic mice. Dev Neurosci 26:435-45
Chen, Qin; Liang, Dongcai; Fromm, Larry D et al. (2004) Inhibition of lens fiber cell morphogenesis by expression of a mutant SV40 large T antigen that binds CREB-binding protein/p300 but not pRb. J Biol Chem 279:17667-73
Xu, Li; Overbeek, Paul A; Reneker, Lixing W (2002) Systematic analysis of E-, N- and P-cadherin expression in mouse eye development. Exp Eye Res 74:753-60
Chen, Qin; Dowhan, Dennis H; Liang, Dongcai et al. (2002) CREB-binding protein/p300 co-activation of crystallin gene expression. J Biol Chem 277:24081-9
Chen, Qin; Ash, John D; Branton, Phil et al. (2002) Inhibition of crystallin expression and induction of apoptosis by lens-specific E1A expression in transgenic mice. Oncogene 21:1028-37

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