Locus-specific transcriptional control of HLA genes.
One remarkable genetic feature of the class I MHC genes is their unparalleled degree of genetic polymorphism and diversity. The polymorphism is reflected by the fact that multiple loci encode class I molecules, and for each locus there are multiple alleles. In the course of investigating the regulation of HLA-A and HLA-B mRNA in human colorectal carcinoma cell lines, we have noticed a noncoordinate expression of the HLA mRNA in some of these cell lines. This observation prompted us to make use of these cell lines to study the locus-specific transcriptional regulation of HLA genes. Bandshift and footprint assays revealed at least three distinct and independent DNA-binding factors that bind to the core regulatory element of the HLA-A and HLB-B gene locus. A "novel" DNA-binding factor recognizing the CCAAT motif seems to be important for locus-specific expression of HLA-A mRNA, whereas a different factor which binds to a Sp1-like sequence is crucial for normal HLA-B mRNA expression. In certain colorectal cancer cell lines, underrepresentation of these locus-specific DNA-binding proteins correlates with the locus-specific down-regulation of HLA mRNA. This observation is further supported by experiments which demonstrated that the locus-specific suppression of exogenously introduced TK-chloramphenicol acetyltransferase DNA constructs, containing the "putative" HLA locus-specific DNA core regulatory sequence, is regulated in a locus-specific manner when introduced into these HLA-A- and HLA-B-deficient human colorectal cell lines.
Soong
T W
TW
Department of Molecular Immunology, National University of Singapore, Kent Ridge.
Hui
K M
KM
D001483:Base Sequence; D015179:Colorectal Neoplasms / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D005805:Genes, MHC Class I; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D012333:RNA, Messenger / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D006680:HLA Antigens; D009687:Nuclear Proteins; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D014157:Transcription Factors