Transforming growth factor beta 1 repression of the HLA-DR alpha gene is mediated by conserved proximal promoter elements.
Transforming growth factor beta 1 (TGF-beta 1) is a pleiotropic cytokine that decreases the expression of class II MHC Ag in the melanoma cell line Hs294T(c). To investigate the mechanism of this repression, we have examined the effect of TGF-beta 1 on expression of the HLA-DR alpha gene. Both the constitutive level of HLA-DR protein and DR alpha mRNA were repressed by treatment with TGF-beta 1. The proximal 176 bp of the DR alpha promoter were sufficient to confer TGF-beta 1 repression on a reporter gene. Deletional and mutational analysis of the DR alpha promoter revealed that the conserved S and X1 promoter elements were important for basal expression of DR alpha and also mediated the down-regulation by TGF-beta 1. Mobility shift assays and in vivo footprinting showed no change in occupancy of the proximal DR alpha promoter after TGF-beta 1 treatment. These results identify the DNA elements that mediate repression of the HLA-DR alpha gene by TGF-beta 1 and suggest that TGF-beta 1 acts at these sites without causing a change in promoter occupancy.
Reimold
A M
AM
Department of Cancer Biology, Harvard School of Public Health, Boston, MA 02115.
Kara
C J
CJ
Rooney
J W
JW
Glimcher
L H
LH
D001483:Base Sequence; D017124:Conserved Sequence; D004586:Electrophoresis; D005786:Gene Expression Regulation; D006684:HLA-DR Antigens / Q000032:analysis / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D016296:Mutagenesis; D011401:Promoter Regions, Genetic; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D006684:HLA-DR Antigens; D016212:Transforming Growth Factor beta