Coordinate regulation of the human TAP1 and LMP2 genes from a shared bidirectional promoter.

Wright, Kenneth L.; White, Leigh C.; Kelly, Anita M.; Beck, Stephan; Trowsdale, John; Ting, Jenny P.Y.

doi:10.1084/jem.181.4.1459

Cited by 219 publications

(149 citation statements)

References 73 publications

(86 reference statements)

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“…It appears that in the mouse, the TAP2-associated IRF1 binding element mediates both the constitutive and the induced expression of TAP2 via its binding to IRF1. However, while the activity of the human TAP1 (as well as of the human LMP2 gene) promoter is assisted by factors binding to the NF-B and Sp1 elements (7,8), these elements are not obvious in the 5ЈUTR and flanking region of the mouse TAP2 gene (Fig. 2C).…”

Section: Discussionmentioning

confidence: 99%

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Organization and Functional Analysis of the Mouse Transporter Associated with Antigen Processing 2 Promoter

Arons

Kunin

Schechter

et al. 2001

The Journal of Immunology

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In accordance with the key role of MHC class I molecules in the adaptive immune response against viruses, they are expressed by most cells, and their expression can be enhanced by cytokines. The assembly and cell surface expression of class I complexes depend on a continuous peptide supply. The peptides are generated mainly by the proteasome and are transported to the endoplasmic reticulum by a peptide transport pump consisting of two subunits, TAP1 and TAP2. The proteasome low molecular weight polypeptide (2 and 7), as well as TAP (1 and 2) genes, are coordinately regulated and are induced by IFNs. Despite this coordinate regulation, examination of tumors shows that these genes can be discordantly down-regulated. In pursuing a molecular explanation for these observations, we have characterized the mouse TAP2 promoter region and 5′-flanking sequence. We show that the 5′ untranslated regions of TAP2 genes have a characteristic genomic organization that is conserved in both the mouse and the human. The mouse TAP2 promoter belongs to a class of promoters that lack TATA boxes but contain a MED1 (multiple start site element downstream) sequence. Accordingly, transcription is initiated from multiple sites within a 100-nucleotide window. An IFN regulatory factor 1 (IRF1)/IRF2 binding site is located in this region and is involved in both basal and IRF1-induced TAP2 promoter activity. The implication of the extensive differences found among the promoters of class I heavy chain, low molecular weight polypeptide, and TAP genes, all encoding proteins involved in Ag presentation, is discussed.

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Section: Discussionmentioning

confidence: 99%

“…Similarly to the TAP1 and LMP2 genes (7,19), the TAP2 promoter lacks a TATA box. Accordingly, nine transcription start sites were detected by the 5ЈRACE method (Fig.…”

Section: Discussionmentioning

confidence: 99%

Organization and Functional Analysis of the Mouse Transporter Associated with Antigen Processing 2 Promoter

Arons

Kunin

Schechter

et al. 2001

The Journal of Immunology

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“…A bidirectional promoter drives LMP2 and TAP1 expression, with LMP2 situated in an opposite transcriptional orientation in relation to the other three genes of the cluster. 47 PCR primer sequences, PCR amplification conditions and restriction fragment sizes are listed in Table 1.…”

Section: Snp Markersmentioning

confidence: 99%

Genes of the LMP/TAP cluster are associated with the human autoimmune disease vitiligo

She

McCormack

2003

Genes Immun

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Genes within the class II region of the major histocompatibility complex (MHC), including genes involved in antigen processing and presentation, have been reported to be associated with several autoimmune diseases. We report here that the LMP/TAP gene region is significantly associated with vitiligo, a disorder in which biochemical defects and/or autoimmune destruction cause melanocyte loss and resulting skin depigmentation. Case/control analyses revealed genetic association of vitiligo in Caucasian patients with an early age of onset with the transporter associated with antigen processing-1 (TAP1) gene. A familybased association method revealed biased transmission of specific alleles from heterozygous parents to affected offspring for the TAP1 gene, as well as for the closely linked LMP2 and LMP7 genes encoding subunits of the immunoproteasome. No association with vitiligo was found for the MECL1 gene, which encodes a third immunoproteasome subunit and is unlinked to the MHC class II region. These results suggest a possible role for the MHC class I antigen processing and/or presentation pathway in the antimelanocyte autoimmune response involved in vitiligo pathogenesis.

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“…6A). Although the IRF-E site of the bidirectional TAP1/LMP2 promoter can be aligned with the PRDM1/Blimp-1 consensus sequence (19,28,41,43), there was poor association of PRDM1 with the TAP1/ LMP2 promoter (Fig. 6, A and D).…”

Section: Ifn-␥-mediated Induction Of Ciita-piv Is Repressed In the Mymentioning

confidence: 99%

“…To address whether the difference in TAP1/ LMP2 and CIITA-pIV regulation was reflected in differential promoter occupancy, we performed ChIP analysis on chromatin prepared from untreated and IFN-␥-treated H929 cells. Samples were immunoprecipitated with control Ab, Ab to PRDM1, IRF-1, or IRF-2, and the fraction of precipitated input chromatin from the CIITA-pIV and the bidirectional TAP1/LMP2 promoter was assessed (41,43). The promoter of the cytokeratin-10 gene (KRT-10), which lacks an IRF-E sequence and is not expressed in lymphoid lineage cells was amplified as a negative control to assess nonspecific binding.…”

Section: Ifn-␥-mediated Induction Of Ciita-piv Is Repressed In the Mymentioning

confidence: 99%

Repression of IFN-γ Induction of Class II Transactivator: A Role for PRDM1/Blimp-1 in Regulation of Cytokine Signaling

Tooze

Stephenson

Doody

2006

The Journal of Immunology

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MHC class II is expressed in restricted lineages and is modulated in response to pathogens and inflammatory stimuli. This expression is controlled by MHC CIITA, which is transcribed from multiple promoters. Although factors required for induction of CIITA are well characterized, less is known about the mechanisms leading to repression of this gene. During plasma cell differentiation, B lymphocyte-induced maturation protein-1 (PRDM1/Blimp-1) represses promoter (p)III of CIITA, responsible for constitutive expression in B cells. pIV is inducible by IFN-γ in epithelia, macrophages and B cells. An IFN regulatory factor-element (IRF-E) in CIITA-pIV, which is bound by IRF-1 and IRF-2, is necessary for this response. This site matches the PRDM1/Blimp-1 consensus binding site, and PRDM1/Blimp-1 is expressed in cell lineages in which this promoter is operative. We, therefore, investigated whether PRDM1 regulates CIITA-pIV and found that PRDM1 bound to CIITA-pIV in vivo and the IRF-E in vitro. PRDM1 repressed IFN-γ-mediated induction of a CIITA-pIV luciferase reporter in a fashion dependent on an intact consensus sequence and competes with IRF-1/IRF-2 for binding to the IRF-E and promoter activation. In human myeloma cell lines that express IRFs, PRDM1 occupancy of CIITA-pIV was associated with resistance to IFN-γ stimulation, while short interfering RNA knockdown of PRDM1 led to up-regulation of CIITA. Our data indicate that PRDM1 is a repressor of CIITA-pIV, identifying a target of particular relevance to macrophages and epithelia. These findings support a model in which PRDM1/Blimp-1 can modulate the cellular response to IFN-γ by competing with IRF-1/IRF-2 dependent activation of target promoters.

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Coordinate regulation of the human TAP1 and LMP2 genes from a shared bidirectional promoter.

Cited by 219 publications

References 73 publications

Organization and Functional Analysis of the Mouse Transporter Associated with Antigen Processing 2 Promoter

Organization and Functional Analysis of the Mouse Transporter Associated with Antigen Processing 2 Promoter

Genes of the LMP/TAP cluster are associated with the human autoimmune disease vitiligo

Repression of IFN-γ Induction of Class II Transactivator: A Role for PRDM1/Blimp-1 in Regulation of Cytokine Signaling

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