Regulation of the human leukocyte-derived arginine aminopeptidase/endoplasmic reticulum-aminopeptidase 2 gene by interferon-gamma.
The leukocyte-derived arginine aminopeptidase (L-RAP) is the second aminopeptidase localized in the endoplasmic reticulum (ER) processing antigenic peptides presented to major histocompatibility complex (MHC) class I molecules. In this study, the genomic organization of the gene encoding human L-RAP was determined and the regulatory mechanism of its expression was elucidated. The entire genomic structure of the L-RAP gene is similar to both placental leucine aminopeptidase (P-LAP) and adipocyte-derived leucine aminopeptidase (A-LAP) genes, confirming the close relationship of these three enzymes. Interferon (IFN)-gamma up-regulates the expression of the L-RAP gene. Deletion and site-directed mutagenic analyses of the 5'-flanking region of the L-RAP gene and electrophoretic mobility shift assay indicated that while interferon regulatory factor (IRF)-2 is important in the basal condition, IRF-1 is the primary regulator of IFN-gamma-mediated augmentation of the gene expression. In addition, PU.1, a member of the E26 transformation-specific family of transcription factors, also plays a role in the regulation of gene expression. The maximum expression of the gene was achieved by coexpression of IRF-1 and PU.1 in HEK293 cells and IRF-2 suppressed the IRF-1-mediated enhancement of gene expression, suggesting that IFN-gamma-induced L-RAP gene expression is cooperatively regulated by IRFs and PU.1 transcription factors.
Tanioka
Toshihiro
T
Laboratory of Cellular Biochemistry, RIKEN, Wako, Saitama, Japan.
Hattori
Akira
A
Mizutani
Shigehiko
S
Tsujimoto
Masafumi
M
D000626:Aminopeptidases / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D013997:Time Factors
D007371:Interferon-gamma; D000626:Aminopeptidases; C019721:aminopeptidase B