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J. Biol. Chem., Vol. 280, Issue 30, 27998-28006, July 29, 2005

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Human Aldehyde Dehydrogenase 3A1 Inhibits Proliferation and Promotes Survival of Human Corneal Epithelial Cells^*

Aglaia Pappa, Donald Brown¶, Yiannis Koutalos||, James DeGregori**, Carl White, and Vasilis Vasiliou

From the Molecular Toxicology and Environmental Health Sciences Program, University Colorado Health Sciences Center, Denver, Colorado 80262, ^¶Department of Ophthalmology, University of California, Irvine, California 92868, ^||Department of Ophthalmology, Medical University of South Carolina, Charleston, South Carolina 29425, ^**Department of Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, Denver, Colorado 80262, and Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado 80206

Aldehyde dehydrogenase 3A1 (ALDH3A1) is a NAD(P)⁺-dependent enzyme that is highly expressed in mammalian corneal epithelial cells and has been shown to protect against UV- and 4-hydroxynonenal-induced cellular damage, mainly by metabolizing toxic lipid peroxidation aldehydes. Here we report a novel function of ALDH3A1 as a negative cell cycle regulator. We noticed a reduction in ALDH3A1 gene expression in actively proliferating primary human corneal epithelium explant cultures, indicating that ALDH3A1 expression is inversely correlated with replication. To examine this further, a human corneal epithelial cell line (HCE) lacking endogenous ALDH3A1 was stably transfected to express ALDH3A1 at levels similar to those found in vivo. ALDH3A1-transfected cells exhibited an elongated cell cycle, decreased plating efficiency, and reduced DNA synthesis compared with the mock-transfected cells. These effects were associated with reduced cyclin A- and cyclin B-dependent kinase activities and reduced phosphorylation of the retinoblastoma protein (pRb) as well as decreased protein levels of cyclins A, B, and E, the transcription factor E2F1, and the cyclin-dependent kinase inhibitor p21. These observations were further expanded and confirmed on human keratinocyte cells (NCTC-2544) overexpressing ALDH3A1. Consistent with a protective role of an elongated cell cycle, ALDH3A1-transfected cells exhibited increased resistance to the cytotoxic effects of the DNA-damaging agents mitomycin C and Vp-16. Immunohistochemistry and biochemical fractionation revealed that ALDH3A1 is localized both in the nucleus and cytosol of ALDH3A1-transfected cells, implying a possible association between the nuclear localization of the enzyme and its proliferation-suppressive functions. In conclusion, these results suggest that ALDH3A1 may protect corneal epithelial cells against oxidative damage not only through its metabolic function but also by prolonging the cell cycle.

Received for publication, April 5, 2005 , and in revised form, May 10, 2005.

^* This work was supported by National Institute Grants EY11490 (to V. V.) and T32 AA07464 (to A. P.), by Discovery Fund for Eye Research (to D. B.), and by an unrestricted grant from Research to Prevent Blindness (to D. B.). 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: Dept. of Molecular Biology and Genetics, Democritus University of Thrace, Dimitras 19, 68100 Alexandroupolis, Greece.

To whom correspondence should be addressed: Molecular Toxicology and Environmental Health Sciences Program, Dept. of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, CO 80262. Tel.: 303-315-6253; Fax: 303-315-6281; E-mail: vasilis.vasiliou{at}uchsc.edu.

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