HLA-G transactivation by cAMP-response element-binding protein (CREB). An alternative transactivation pathway to the conserved major histocompatibility complex (MHC) class I regulatory routes.
The expression of HLA-G in extravillous cytotrophoblast cells coincides with a general lack of classical major histocompatibility complex (MHC) class I expression in this tissue. This differential expression of HLA-G and classical HLA class I molecules in trophoblasts suggests a tight transcriptional control of MHC class I genes. Transactivation of the classical MHC class I genes is mediated by two groups of juxtaposed cis-acting elements that can be viewed as regulatory modules. Both modules are divergent in HLA-G, rendering this gene unresponsive to NF-kappaB, IRF1, and class II transactivator (CIITA)-mediated induction pathways. In this study, we searched for alternative regulatory elements in the 1438-bp HLA-G promoter region. HLA-G was not responsive to interferon-alpha (IFNalpha), IFNbeta, or IFNgamma, despite the presence of an upstream ISRE binding IRF1 in vitro. However, the HLA-G promoter contains three CRE/TRE elements with binding affinity for CREB/ATF and Fos/Jun proteins both in vitro and in vivo. In transient transfection assays, it was shown that HLA-G transactivation is regulated by CREB, CREB-binding protein (CBP), and p300. Moreover, immunohistochemical analysis demonstrated that HLA-G is co-expressed with CREB and CBP in extravillous cytotrophoblasts, revealing the in vivo relevance of this transactivation pathway. This implies a unique regulation of HLA-G transcription among the MHC class I genes.
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
Sam J P
SJ
Gobin
Paula
P
Biesta
Jurriaan E M
JE
de Steenwinkel
Gert
G
Datema
Peter J
PJ
van den Elsen
D002843:Chromatin / Q000378:metabolism; D017930:Genes, Reporter; D006680:HLA Antigens / Q000096:biosynthesis* / Q000235:genetics*; D059951:HLA-G Antigens; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis* / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D016898:Interferon-alpha / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D019169:Jurkat Cells; D008285:Major Histocompatibility Complex; D008957:Models, Genetic; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
D002843:Chromatin; D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; D016898:Interferon-alpha; D014157:Transcription Factors; D016899:Interferon-beta; D007371:Interferon-gamma