Human HMG box transcription factor HBP1: a role in hCD2 LCR function

Zhuma, T; Tyrrell, R; Sekkali, Belaïd; Skavdis, George; Saveliev, Alexander; Tolaini, Mauro; Roderick, Kathleen; Norton, Trisha; Smerdon, Stephen J.; Sedgwick, Steven G.; Festenstein, Richard; Kioussis, Dimitris

doi:10.1093/emboj/18.22.6396

Cited by 57 publications

(52 citation statements)

References 63 publications

(95 reference statements)

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“…The HBP1 high-affinity binding site sequence (5 0 -TTCA TTCATTCA-3 0 ) was identified previously (Zhuma et al, 1999;Berasi et al, 2004). In our searches, we identified an HBP1 high-affinity binding site in the MIF promoter ( Figure 1a).…”

Section: Hbp1 Represses Mif Transcription In a Dna-bindingdependent Mmentioning

confidence: 64%

“…The HBP1 high-affinity DNA-binding site sequence (5 0 -TTC ATTCATTCA-3 0 , Zhuma et al, 1999) was used to query the Regulatory Sequence Analysis Tools using the Genome Scale Pattern Matching program (http://rsat.ulb.ac.be/rsat/). The results of this analysis showed that the MIF gene promoter contains a large HBP1-binding site at positions À811 to À792 relative to the transcriptional start site (see Figure 1a).…”

Section: Database Searchesmentioning

confidence: 99%

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Macrophage migration inhibitory factor is a direct target of HBP1-mediated transcriptional repression that is overexpressed in prostate cancer

et al. 2010

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Macrophage migration inhibitory factor (MIF) is a welldescribed proinflammatory mediator. MIF overexpression has been observed in many tumors and is implicated in oncogenic transformation and tumor progression. However, the molecular mechanisms responsible for regulating MIF expression remain poorly understood. In this study, we showed that the transcriptional repressor HBP1 (HMG box-containing protein 1) negatively regulates MIF expression. We first identified a large high-affinity HBP1 DNA-binding element at positions À811 to À792 from the transcriptional start site within the MIF promoter by computer analysis. Reporter analyses showed that this element was required for HBP1-mediated transcriptional repression. Furthermore, HBP1 associated with the MIF promoter in vivo and repressed endogenous MIF gene expression. Consistent with HBP1-mediated repression of MIF, low levels of HBP1 expression were associated with high levels of MIF expression in prostate cancer samples. Importantly, HBP1-mediated repression of MIF inhibited tumorigenic growth and invasion, and the repressive effect of HBP1 on tumorigenic growth and invasion could be partially rescued by the addition of recombinant MIF to the culture medium. Finally, prostate tumor samples with low HBP1 and high MIF expression were associated with a significant decrease in relapse-free survival. Taken together, these results indicated that HBP1 directly inhibited MIF gene transcription, and suggested that the loss of HBP1 expression or activity may contribute to the upregulation of MIF expression in prostate tumor tissue.

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Section: Hbp1 Represses Mif Transcription In a Dna-bindingdependent Mmentioning

confidence: 64%

Section: Database Searchesmentioning

confidence: 99%

Macrophage migration inhibitory factor is a direct target of HBP1-mediated transcriptional repression that is overexpressed in prostate cancer

et al. 2010

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“…Nevertheless, their effect on transgene expression in the chromatin of the whole animal is now well documented. Such elements include HS3 of the ␤-globin LCR (27), HSS3 of the CD2 LCR (44), and the facilitator elements of the adenosine deaminase LCR (38). We have also recently described such an element in the TCR␣ LCR.…”

Section: Discussionmentioning

confidence: 99%

“…Extensive computer and manual inspection revealed no significant homology between this region and the core sequences of the ␤-globin HS3 element. Recently, a sequence involved in the function of HSS3 of the CD2 LCR was described (44). This sequence binds a ubiquitously expressed factor called HMG-BOX containing protein-1 (HBP-1).…”

Section: Discussionmentioning

confidence: 99%

Function and Factor Interactions of a Locus Control Region Element in the Mouse T Cell Receptor-α/Dad1 Gene Locus

Ortiz

Harrow

Cado

et al. 2001

The Journal of Immunology

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Locus control regions (LCRs) refer to cis-acting elements composed of several DNase I hypersensitive sites, which synergize to protect transgenes from integration-site dependent effects in a tissue-specific manner. LCRs have been identified in many immunologically important gene loci, including one between the TCRδ/TCRα gene segments and the ubiquitously expressed Dad1 gene. Expression of a transgene under the control of all the LCR elements is T cell specific. However, a subfragment of this LCR is functional in a wide variety of tissues. How a ubiquitously active element can participate in tissue-restricted LCR activity is not clear. In this study, we localize the ubiquitously active sequences of the TCR-α LCR to an 800-bp region containing a prominent DNase hypersensitive site. In isolation, the activity in this region suppresses position effect transgene silencing in many tissues. A combination of in vivo footprint examination of this element in widely active transgene and EMSAs revealed tissue-unrestricted factor occupancy patterns and binding of several ubiquitously expressed transcription factors. In contrast, tissue-specific, differential protein occupancies at this element were observed in the endogenous locus or full-length LCR transgene. We identified tissue-restricted AML-1 and Elf-1 as proteins that potentially act via this element. These data demonstrate that a widely active LCR module can synergize with other LCR components to produce tissue-specific LCR activity through differential protein occupancy and function and provide evidence to support a role for this LCR module in the regulation of both TCR and Dad1 genes.

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“…HMG box-containing protein 1 (HBP1) is homologous to the sequence-specific high mobility group (HMG) family of transcriptional factors (Yee et al, 1999;Zhuma et al, 1999;Berasi et al, 2004). We have previously isolated HBP1 as a retinoblastoma partner and have determined that it functions as a proliferation regulator by inhibiting oncogenic pathways as a transcriptional repressor (Lavender et al, 1997;Tevosian et al, 1997;Shih et al, 1998Shih et al, , 2001Lemercier et al, 2000;Smith et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Transcriptional factor HBP1 targets P16INK4A, upregulating its expression and consequently is involved in Ras-induced premature senescence

Wang

Liu

et al. 2010

Oncogene

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Oncogene-mediated premature senescence has emerged as a potential tumor-suppressive mechanism in early cancer transitions. Many studies showed that Ras and p38 mitogen-activated protein kinase (MAPK) participate in premature senescence. Our previous work indicated that the HMG box-containing protein 1 (HBP1) transcription factor is involved in Ras-and p38 MAPK-induced premature senescence, but the mechanism of which has not yet been identified. Here, we showed that the p16 INK4A cyclin-dependent kinase inhibitor is a novel target of HBP1 participating in Ras-induced premature senescence. The promoter of the p16 INK4A gene contains an HBP1-binding site at position À426 to À433 bp from the transcriptional start site. HBP1 regulates the expression of the endogenous p16 INK4A gene through direct sequence-specific binding. With HBP1 expression and the subsequent increase of p16 INK4A gene expression, Ras induces premature senescence in primary cells. The data suggest a model in which Ras and p38 MAPK signaling engage HBP1 and p16 INK4A to trigger premature senescence. In addition, we report that HBP1 knockdown is also required for Ras-induced transformation. All the data indicate that the mechanism of HBP1-mediated transcriptional regulation is important for not only premature senescence but also tumorigenesis.

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Human HMG box transcription factor HBP1: a role in hCD2 LCR function

Cited by 57 publications

References 63 publications

Macrophage migration inhibitory factor is a direct target of HBP1-mediated transcriptional repression that is overexpressed in prostate cancer

Macrophage migration inhibitory factor is a direct target of HBP1-mediated transcriptional repression that is overexpressed in prostate cancer

Function and Factor Interactions of a Locus Control Region Element in the Mouse T Cell Receptor-α/Dad1 Gene Locus

Transcriptional factor HBP1 targets P16INK4A, upregulating its expression and consequently is involved in Ras-induced premature senescence

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