ING3 promotes UV-induced apoptosis via Fas/caspase-8 pathway in melanoma cells.
The novel ING tumor-suppressor family proteins (ING1-5) have been discovered during the past decade and are recognized as the regulators of transcription, cell cycle checkpoints, DNA repair, apoptosis, cellular senescence, angiogenesis, and nuclear phosphoinositide signaling. ING proteins contain a few conserved domains, including plant homeodomain motif, nuclear localization signal, and potential chromatin regulatory domain, suggesting that the ING family proteins may share common biological functions. ING3 has been shown to modulate p53-mediated transcription, cell cycle control, and apoptosis, possibly by modulating the NuA4 complex histone acetyltransferase activity. Because ING1b and ING2 have been shown to be involved in cellular stress responses such as nucleotide excision repair and apoptosis after UV irradiation, we investigated whether ING3 also mediated UV-induced apoptosis. We found that ING3 expression was rapidly induced by UV irradiation at both mRNA and protein levels. Using the stable clones of melanoma cells overexpressing ING3, we showed that overexpression of ING3 significantly promoted UV-induced apoptosis. Unlike its homologues ING1b and ING2, ING3-increased apoptosis was independent of functional p53. Furthermore, ING3 did not affect the expression of mitochondrial proteins but increased the cleavage of Bid and caspases-8, -9, and -3. Moreover, ING3-mediated apoptosis was blocked by inhibition of caspase-8 or Fas activation. In addition, ING3 up-regulated Fas expression at both mRNA and protein levels. Knock down of ING3 decreased UV-induced apoptosis remarkably. These data indicate that ING3 plays an important role in cellular response to UV irradiation by enhancing UV-induced apoptosis through the activation of Fas/caspase-8 pathway.
Wang
Yemin
Y
Department of Dermatology and Skin Science, Jack Bell Research Centre, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada.
Li
Gang
G
D017209:Apoptosis / Q000528:radiation effects*; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism*; D016147:Genes, Tumor Suppressor; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D014466:Ultraviolet Rays; D019014:fas Receptor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D018398:Homeodomain Proteins; C459806:ING3 protein, human; D034741:RNA, Small Interfering; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D019014:fas Receptor; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases