Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0849640 (skin damage)
 1,516 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 (RARgamma) and retinoid X receptor alpha (RXRalpha). We found that exposure of cultured primary human keratinocytes to UV irradiation (30 mJ/cm2) substantially reduced (50-90%) RARgamma and RXRalpha mRNA and protein within 8 h. The rates of disappearance of RARgamma and RXRalpha proteins after UV exposure or treatment with the protein synthesis inhibitor cycloheximide were similar. UV irradiation did not increase the rate of breakdown of RARgamma or RXRalpha but rather reduced their rate of synthesis. The addition of proteasome inhibitors MG132 and LLvL, but not the lysosomal inhibitor E64, prevented loss of RARgamma and RXRalpha 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 RARgamma and RXRalpha proteins in vitro. Furthermore, RARgamma and RXRalpha were polyubiquitinated in intact cells. RXRalpha 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 RXRalpha 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 RXRalpha. These results demonstrate that loss of RARgamma and RXRalpha 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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PMID:Ubiquitin/proteasome pathway regulates levels of retinoic acid receptor gamma and retinoid X receptor alpha in human keratinocytes. 1078 91

There is considerable evidence that the excessive ultraviolet radiation B (UVB) from sunlight is implicated in skin damage, ultimately inducing the death of keratinocytes. The UVB-induced apoptotic pathways are tightly regulated by the balance between pro-apoptotic and anti-apoptotic molecules. Among them, modulations of Bcl2 family proteins are important to decide the fate of UVB-irradiated cells. If the apoptotic pathway does not work properly, the damaged cells have a chance to transform into a carcinoma, such as basal cell carcinoma or squamous cell carcinoma of the skin. To develop a strategy of inducing apoptosis of skin cancer cells, the current study was performed to investigate the apoptotic pathway, especially focused on Bcl2 family proteins, in curcumin or UVB-treated basal cell carcinoma cell lines. Our data showed that the decreased proliferation rates and apoptotic DNA laddering were clearly observed in UVB irradiation, but not markedly observed in curcumin treatment. The decreased expression of Bcl-XL, which is involved in protection of apoptosis, was also clearly observed in UVB-irradiated cells without markedly changing mRNA levels. However, the expression of Bax or Bcl2 were not markedly changed by UVB-irradiation. The decreased expression of Bcl-XL protein after UVB treatment was partially restored in the presence of MG132, which is an inhibitor of proteasome, implying that the down-regulation of Bcl-XL may be regulated by the proteasome-mediated degradation. Our data demonstrated that the expression of Bcl-XL protein was decreased by proteasome-mediated degradation prior to change of mRNA level in UVB-induced apoptotic basal cell carcinoma cell lines, thereby these results will offer fundamental information to develop a strategy of inducing apoptosis of skin cancer cells.
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PMID:Bcl-XL protein is markedly decreased in UVB-irradiated basal cell carcinoma cell lines through proteasome-mediated degradation. 1921 27

When cells encounter genotoxic stress, sensors for DNA lesions stabilize and activate p53; the signals involved, however, are largely unclear. Inorganic arsenite is a ubiquitous environmental contaminant associated with an increased risk of lung and skin damage and cancer. Although DNA double-strand breaks and apoptosis may relate to arsenite-induced damage and carcinogenesis, the mechanism of action remains obscure. Here, we find that, in human embryo lung fibroblast (HELF) cells, arsenite induces the activation of dependent protein kinase catalytic subunit (DNA-PKcs), which then phosphorylates and activates c-Jun N-terminal kinases 2 (JNK2), but not JNK1. As a positive regulator of p53, JNK2 binds to p53 and prevents p53 from murine double minute 2 (mdm2)-mediated, ubiquitin-proteasome-dependent degradation. Knockdown of DNA-PKcs/JNK2 signal pathway or p53 reduces apoptosis but elevates the DNA damage induced by a high level of arsenite. These results suggest that DNA-PKcs-mediated stabilization of p53 by JNK2 is involved in arsenite-induced DNA damage and apoptosis.
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PMID:DNA-PKcs-mediated stabilization of p53 by JNK2 is involved in arsenite-induced DNA damage and apoptosis in human embryo lung fibroblast cells. 2236 12