Defective MHC class I antigen surface expression promotes cellular survival through elevated ER stress and modulation of p53 function.
Defects in Major Histocompatibility class I cell surface expression is thought to allow escape of tumor cells from immune surveillance. Hitherto, it is unclear whether this deficiency confers immune-independent survival advantage. We show here that class I cell surface expression deficiency due to defects in beta2 microglobulin or the transporter-associated with antigen processing (TAP) results in resistance to apoptosis in response to various cytotoxic signals. Reduced apoptosis correlated with altered p53 activation, which was due to compromised nuclear translocation of p53. Binding of p53 to glycogen synthase kinase-3beta (GSK3beta), which is known to phosphorylate and lead to cytoplasmic sequestration of p53, was enhanced in these cells. Consistently, endoplasmic reticulum (ER) stress, which promotes binding of p53 to GSK3beta was constitutively elevated in the absence of class I cell surface expression. Taken together, the results suggest a non-immunological causal role for defective class I cell surface expression in regulating cellular survival in a p53-dependent manner, through the upregulation of ER stress, which could be another mechanism leading to carcinogenesis.
Sabapathy
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Laboratory of Molecular Carcinogenesis, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore. cmrksb@nccs.com.sg
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D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D017353:Gene Deletion; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009153:Mutagens / Q000633:toxicity; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D001613:beta 2-Microglobulin / Q000235:genetics
D018528:ATP-Binding Cassette Transporters; D015395:Histocompatibility Antigens Class I; D009153:Mutagens; D016159:Tumor Suppressor Protein p53; D001613:beta 2-Microglobulin; C477327:transporter associated with antigen processing (TAP)