title: Regulation of interlocking gene regulatory network subcircuits by a small molecule inhibitor of retinoblastoma protein (RB) phosphorylation: cancer cell expression of HLA-DR.
abstract: The induction of the major histocompatibility (MHC), antigen-presenting class II molecules by interferon-gamma, in solid tumor cells, requires the retinoblastoma tumor suppressor protein (Rb). In the absence of Rb, a repressosome blocks the access of positive-acting, promoter binding proteins to the MHC class II promoter. However, a complete molecular linkage between Rb expression and the disassembly of the MHC class II repressosome has been lacking. By treating A549 lung carcinoma cells with a novel small molecule that prevents phosphorylation-mediated, Rb inactivation, we demonstrate that Rb represses the synthesis of an MHC class II repressosome component, YY1. The reduction in YY1 synthesis correlates with the advent of MHC class II inducibility; with loss of YY1 binding to the promoter of the HLA-DRA gene, the canonical human MHC class II gene; and with increased Rb binding to the YY1 promoter. These results support the concept that the Rb gene regulatory network (GRN) subcircuit that regulates cell proliferation is linked to a GRN subcircuit regulating a tumor cell immune function.
authors.affiliation: Drug Discovery Program, Department of Oncologic Sciences, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA.
authors.forename: Smitha
authors.initials: S
authors.lastname: Pillai
authors.forename: Karoly
authors.initials: K
authors.lastname: Szekeres
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Lawrence
authors.forename: Srikumar P
authors.initials: SP
authors.lastname: Chellappan
authors.forename: George
authors.initials: G
authors.lastname: Blanck
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm; D059805:HLA-DR alpha-Chains / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000235:genetics / Q000276:immunology; D011401:Promoter Regions, Genetic; D016160:Retinoblastoma Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D050986:YY1 Transcription Factor / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology
chemical_list: D059805:HLA-DR alpha-Chains; D016160:Retinoblastoma Protein; D050986:YY1 Transcription Factor; C494698:YY1 protein, human