| Human aldehyde dehydrogenase 3A1 inhibits proliferation and promotes survival of human corneal epithelial cells. | |
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MedLine Citation:
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PMID: 15905174 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Aglaia Pappa; Donald Brown; Yiannis Koutalos; James DeGregori; Carl White; Vasilis Vasiliou |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. Date: 2005-05-19 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 280 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2005 Jul |
Date Detail:
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Created Date: 2005-07-25 Completed Date: 2005-09-22 Revised Date: 2011-09-22 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 27998-8006 Citation Subset: IM |
Affiliation:
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Molecular Toxicology and Environmental Health Sciences Program, University Colorado Health Sciences Center, Denver, Colorado 80262, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Aldehyde Dehydrogenase
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metabolism,
physiology* Aldehydes / pharmacology Apoptosis Blotting, Western Bromodeoxyuridine / pharmacology Cell Cycle Cell Cycle Proteins / metabolism Cell Nucleus / metabolism Cell Proliferation Cell Survival Cells, Cultured Cornea / cytology, metabolism Cyclin A / metabolism Cyclin B / metabolism Cyclin E / metabolism Cytosol / metabolism DNA / metabolism DNA Damage DNA Fragmentation DNA-Binding Proteins / metabolism E2F Transcription Factors E2F1 Transcription Factor Epithelial Cells / cytology* Gene Expression Regulation Humans Immunohistochemistry Keratinocytes / cytology Microscopy, Confocal Microscopy, Fluorescence Mitomycin / pharmacology Oxidative Stress Protein Kinases / metabolism Retinoblastoma Protein / metabolism Time Factors Transcription Factors / metabolism Transfection Ultraviolet Rays |
| Grant Support | |
ID/Acronym/Agency:
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EY11490/EY/NEI NIH HHS; R01 CA077314-07/CA/NCI NIH HHS; T32 AA07464/AA/NIAAA NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Aldehydes; 0/Cell Cycle Proteins; 0/Cyclin A; 0/Cyclin B; 0/Cyclin E; 0/DNA-Binding Proteins; 0/E2F Transcription Factors; 0/E2F1 Transcription Factor; 0/E2F1 protein, human; 0/Retinoblastoma Protein; 0/Transcription Factors; 29343-52-0/4-hydroxy-2-nonenal; 50-07-7/Mitomycin; 59-14-3/Bromodeoxyuridine; 9007-49-2/DNA; EC 1.2.1.3/ALDH3A1 protein, human; EC 1.2.1.3/Aldehyde Dehydrogenase; EC 2.7.-/Protein Kinases; EC 2.7.1.-/histone H1 kinase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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