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[Cancer Research 60, 2247-2252, April 15, 2000]
© 2000 American Association for Cancer Research

Molecular Biology and Genetics

Ubiquitin/Proteasome Pathway Regulates Levels of Retinoic Acid Receptor {gamma} and Retinoid X Receptor {alpha} in Human Keratinocytes1

Mohamed Boudjelal, Zengquan Wang, John J. Voorhees and Gary J. Fisher2

Department of Dermatology, University of Michigan, Ann Arbor, Michigan 48109

Repeated exposure of human skin to solar UV radiation leads to premature aging (photoaging) and skin cancer. UV-induced skin damage can be ameliorated by all-trans retinoic acid treatment. The actions of retinoic acid in skin keratinocytes are mediated primarily by nuclear retinoic acid receptor {gamma} (RAR{gamma}) and retinoid X receptor {alpha} (RXR{alpha}). We found that exposure of cultured primary human keratinocytes to UV irradiation (30 mJ/cm2) substantially reduced (50–90%) RAR{gamma} and RXR{alpha} mRNA and protein within 8 h. The rates of disappearance of RAR{gamma} and RXR{alpha} proteins after UV exposure or treatment with the protein synthesis inhibitor cycloheximide were similar. UV irradiation did not increase the rate of breakdown of RAR{gamma} or RXR{alpha} but rather reduced their rate of synthesis. The addition of proteasome inhibitors MG132 and LLvL, but not the lysosomal inhibitor E64, prevented loss of RAR{gamma} and RXR{alpha} proteins after exposure of keratinocytes to either UV radiation or cycloheximide. Soluble extracts from nonirradiated or UV-irradiated keratinocytes possessed similar levels of proteasome activity that degraded RAR{gamma} and RXR{alpha} proteins in vitro. Furthermore, RAR{gamma} and RXR{alpha} were polyubiquitinated in intact cells. RXR{alpha} was found to contain two proline, glutamate/aspartate, serine, and threonine (PEST) motifs, which confer rapid turnover of many short-lived regulatory proteins that are degraded by the ubiquitin/proteasome pathway. However, the PEST motifs in RXR{alpha} did not function to regulate its stability, because deletion of the PEST motifs individually or together did not alter ubiquitination or proteasome-mediated degradation of RXR{alpha}. These results demonstrate that loss of RAR{gamma} and RXR{alpha} proteins after UV irradiation results from degradation via the ubiquitin/proteasome pathway. Taken together, the data here indicate that ubiquitin/proteasome-mediated breakdown is an important mechanism regulating the levels of nuclear retinoid receptors.




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