A 3′-Transcribed Region of the <i>HLA-A2</i> Gene Mediates Posttranscriptional Stimulation by IFN-γ

Snyder, Steven R.; Waring, Jeffrey F.; Sheng, Zhaoxue; Kaplan, Sarah; Schultz, Julie M.; Ginder, Gordon D.

doi:10.4049/jimmunol.166.6.3966

Cited by 11 publications

(14 citation statements)

References 57 publications

(63 reference statements)

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“…The level of expression of CAT mRNA from a CAT-HLA-A 3Ј IRE construct in SK-N-MC cells increased 6-fold after IFN-␥ treatment, while there was no increased expression of CAT mRNA after IFN-␥ treatment of cells containing an identical construct lacking HLA-A sequences (30). To map more precisely the site in HLA-A that is responsible for stimulation by IFN-␥, we extended the deletion of the 3Ј end of HLA-A to 1333 nt.…”

Section: Ifn-␥ Stimulation Of Hla-a2 Expression Requires Only 39 Nt Omentioning

confidence: 95%

“…There is evidence that expression of the HLA-B7 and HLA-A2 genes, as well as the mouse H-2L gene, are regulated posttranscriptionally (28 -32). We have shown previously that the increased expression of HLA-A mRNA in the presence of IFN-␥ occurs almost entirely at the posttranscriptional level in several cell types (30). Sequences required for IFN-␥ induction were shown to reside in a 127-nucleotide (nt) region at the 3Ј end of the HLA-A2-transcribed region, and it was demonstrated that IFN-␥ did not influence 3Ј end formation of the RNA or the half-life of HLA-A mRNA in the cytoplasm (30).…”

Section: H Uman Mhc Class I (Mhc-i)mentioning

confidence: 99%

“…We have shown previously that the increased expression of HLA-A mRNA in the presence of IFN-␥ occurs almost entirely at the posttranscriptional level in several cell types (30). Sequences required for IFN-␥ induction were shown to reside in a 127-nucleotide (nt) region at the 3Ј end of the HLA-A2-transcribed region, and it was demonstrated that IFN-␥ did not influence 3Ј end formation of the RNA or the half-life of HLA-A mRNA in the cytoplasm (30). In this study, we present data demonstrating that the IFN-␥ responsive element consists of two 8-nt sites in a 39-nt region at the 3Ј end of the HLA-A gene.…”

Section: H Uman Mhc Class I (Mhc-i)mentioning

confidence: 99%

“…SK-N-MC cells containing the tetracycline inducible CAT-A2 fusion (30) were treated with tetracycline and IFN-␥ for 24 h, then rinsed with tetracycline-free medium to stop transcription. Cells were harvested for RNA isolation at various times after transcription was halted.…”

Section: Nuclear Half-life Studiesmentioning

confidence: 99%

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Differential IFN-γ Stimulation of HLA-A Gene Expression through CRM-1-Dependent Nuclear RNA Export

Browne

Roesser

Sheng

et al. 2006

The Journal of Immunology

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IFNs regulate most MHC class I genes by stimulating transcription initiation. As shown previously, IFN-γ controls HLA-A expression primarily at the posttranscriptional level. We have defined two 8-base sequences in a 39-nucleotide region in the 3′-transcribed region of the HLA-A gene that are required for the posttranscriptional response to IFN-γ. Stimulation of HLA-A expression by IFN-γ requires nuclear export of HLA-A mRNA by chromosome maintenance region 1 (CRM-1). Treatment of cells with leptomycin B, a specific inhibitor of CRM-1, completely inhibited IFN-γ induction of HLA-A. Expression of a truncated, dominant-negative form of the nucleoporin NUP214/CAN, ΔCAN, that specifically interacts with CRM-1, also prevented IFN-γ stimulation of HLA-A, providing confirmation of the role of CRM-1. Increased expression of HLA-A induced by IFN-γ also requires protein methylation, as shown by the fact that treatment of SK-N-MC cells or HeLa cells with the PRMT1 inhibitor 5′-methyl-5′-thioadenosine abolished the cellular response to IFN-γ. In contrast with HLA-A, IFN-γ-induced expression of the HLA class Ib gene, HLA-E, was not affected by either 5′-methyl-5′-thioadenosine or leptomycin B. These results provide proof of principle that it is possible to differentially modulate the IFN-γ-induced expression of the HLA-E and HLA-A genes, whose products often mediate opposing effects on cellular immunity to tumor cells, pathogens, and autoantigens.

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Section: Ifn-␥ Stimulation Of Hla-a2 Expression Requires Only 39 Nt Omentioning

confidence: 95%

Section: H Uman Mhc Class I (Mhc-i)mentioning

confidence: 99%

Section: H Uman Mhc Class I (Mhc-i)mentioning

confidence: 99%

Section: Nuclear Half-life Studiesmentioning

confidence: 99%

See 2 more Smart Citations

Differential IFN-γ Stimulation of HLA-A Gene Expression through CRM-1-Dependent Nuclear RNA Export

Browne

Roesser

Sheng

et al. 2006

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…2 and 5). An IFN-␥-responsive element in the 3Ј untranslated region of the HLA-A2 transcript may contribute to transcript accumulation (52). The element does not stabilize the mRNA, and the exact nature of its activity remains to be fully characterized.…”

Section: Discussionmentioning

confidence: 99%

Locus-Specific Constitutive and Cytokine-Induced HLA Class I Gene Expression

Johnson

2003

The Journal of Immunology

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Cytokine induction of the MHC class I genes increases the nascent molecules available for binding potentially antigenic peptides. The human H chain loci, HLA-A, -B, and -C, encode highly homologous and polymorphic mRNAs. Here, these transcripts were resolved and measured by competitive PCR of cDNA using locus-specific primers. Endothelial cells expressed many HLA-A and -B, but fewer HLA-C, transcripts. In contrast, HeLa cells expressed many HLA-A and -C, but fewer HLA-B, transcripts. The inflammatory cytokines TNF-α, IFN-β, and IFN-γ induced HLA-B strongly, but HLA-A and -C weakly in both cell types. Combined treatment with IFNs and TNF further increased HLA-A and -B, but not HLA-C transcripts. The constitutive and inducible activities of transfected promoters correlated well with mRNA levels. The weak IFN response of the HLA-A2 promoter was not due to variations in the IFN consensus sequence, the site α, or a 3-bp insertion between them. The HLA-Cw6 promoter was less TNF responsive due to a variant κB enhancer, which also reduced the IFN responses. The NF-κB subunit RelA strongly activated the HLA-A2 and -B7 promoters but only weakly activated the HLA-Cw6 promoter due to the variant κB. Cotransfecting NF-κB1 with RelA further increased activity of the HLA-A2 and -B7, but not HLA-Cw6, promoters. All three promoters were activated by MHC class II trans-activator, but not CREB-binding protein, whereas IFN regulatory factor-1 and -2 weakly activated the HLA-B7 and -Cw6, but not HLA-A2, promoters. These studies illustrate common and locus-specific mechanisms that may be targeted to modulate immune reactions.

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Potential regulatory sequences in the untranslated regions of the baboon MHC class Ib gene, Paan-AG, more closely resemble those in the human MHC class Ia genes than those in the class Ib gene, HLA-G

et al. 2004

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The baboon major histocompatibility complex (MHC) class Ib gene, Paan-AG, is structurally similar to the human MHC class Ia gene, HLA-A, but exhibits characteristics similar to those of the class Ib gene HLA-G. These include limited polymorphism, alternative splicing of a single message, and restricted tissue distribution, with high expression in the placenta. In order to determine whether regulatory elements controlling expression of Paan-AG resemble those of HLA-A or HLA-G, we cloned the 5' and 3' untranslated regions of Paan-AG. Unexpectedly, sequence comparisons showed that potential regulatory elements in Paan-AG strikingly resembled those in HLA-A and differed in major respects from those in HLA-G. Unlike HLA-G, Paan-AG contained an intact interferon-gamma stimulated response element (ISRE) in the promoter. Studies using luciferase reporter assays showed that the Paan-AG ISRE was functional. The basal activity of the Paan-AG ISRE and its response to interferon-gamma was similar to that of class Ia MHC genes. Further, we identified an ISRE in the 3' untranslated region of Paan-AG that is known to be functional in HLA-A2 but is deleted in HLA-G. These experiments predict that functional studies may demonstrate differences in regulation of expression of Paan-AG and HLA-G genes, which could restrict the use of the baboon as a primate model for studying HLA-G expression and function.

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A 3′-Transcribed Region of the HLA-A2 Gene Mediates Posttranscriptional Stimulation by IFN-γ

Cited by 11 publications

References 57 publications

Differential IFN-γ Stimulation of HLA-A Gene Expression through CRM-1-Dependent Nuclear RNA Export

Differential IFN-γ Stimulation of HLA-A Gene Expression through CRM-1-Dependent Nuclear RNA Export

Locus-Specific Constitutive and Cytokine-Induced HLA Class I Gene Expression

Potential regulatory sequences in the untranslated regions of the baboon MHC class Ib gene, Paan-AG, more closely resemble those in the human MHC class Ia genes than those in the class Ib gene, HLA-G

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