HLA class I-mediated induction of cell proliferation involves cyclin E-mediated inactivation of Rb function and induction of E2F activity.
Chronic rejection of transplanted organs is manifested as atherosclerosis of the blood vessels of the allograft. HLA class I Ags have been implicated to play a major role in this process, since signaling via HLA class I molecules can induce the proliferation of aortic endothelial as well as smooth muscle cells. In this study, we show that HLA class I-mediated induction of cell proliferation correlates with inactivation of the Rb protein in the T cell line Jurkat as well as human aortic endothelial cells. HLA class I-mediated inactivation of Rb can be inhibited specifically by neutralizing Abs to basic fibroblast growth factor (bFGF), suggesting a role for FGF receptors in the signaling process. Signaling through HLA class I molecules induced cyclin E-associated kinase activity within 4 h in quiescent endothelial cells, and appeared to mediate the inactivation of Rb. A cdk2 inhibitor, Olomoucine, as well as a dominant-negative cdk2 construct prevented HLA class I-mediated inactivation of Rb; in contrast, dominant-negative cdk4 and cdk6 constructs had no effect. Furthermore, there was no increase in cyclin D-associated kinase activity upon HLA class I ligation, suggesting that cyclin E-dependent kinase activity mediates Rb inactivation, leading to E2F activation and cell proliferation.
Nath
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Department of Pathology, College of Physicians and Surgeons, Columbia University, New York 10032, USA.
Bian
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H
Reed
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Chellappan
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SP
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D019927:Cyclin E / Q000502:physiology*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation / Q000276:immunology; D006131:Growth Inhibitors / Q000494:pharmacology; D006680:HLA Antigens / Q000502:physiology*; D015395:Histocompatibility Antigens Class I / Q000502:physiology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D019169:Jurkat Cells / Q000276:immunology / Q000378:metabolism; D007701:Kinetin; D011687:Purines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D017468:Receptors, Fibroblast Growth Factor / Q000502:physiology; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors* / Q000502:physiology; D056465:Retinoblastoma-Binding Protein 1; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000096:biosynthesis* / Q000378:metabolism; D019014:fas Receptor / Q000502:physiology
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D019927:Cyclin E; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D006131:Growth Inhibitors; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D007093:Imidazoles; D011687:Purines; D011725:Pyridines; D017468:Receptors, Fibroblast Growth Factor; D016160:Retinoblastoma Protein; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D019014:fas Receptor; C090046:olomoucine; D018844:Cyclin-Dependent Kinases; C093642:SB 203580; D007701:Kinetin