Binding and Functional Effects of Transcriptional Factor Sp1 on the Murine Interleukin-6 Promotor

Kang, Shin-Heh; Brown, David A.; Kitajima, Isao; Xu, Xiao; Heidenreich, Olaf; Gryaznov, Sergei M.; Nerenberg, Michael

doi:10.1074/jbc.271.13.7330

Cited by 45 publications

(36 citation statements)

References 53 publications

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“…Sp1 is a ubiquitously expressed transcription factor that binds to GC/GT-rich elements and regulates a variety of genes in a constitutive or inducible manner (43,44). One such motif, the CCACC box, has been shown to be essential for Sp1 binding and promoter function in several genes by invariably activating transcription (35,45,46). Sp1 is a multifunctional protein that can directly interact with the basal transcription complex, as recently shown for the MMP-2 proximal promoter (47), or alternatively function as a more general transcription factor and play an important role in directing tissue-specific expression (48,49).…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel, Functional Genetic Variants in the Human Matrix Metalloproteinase-2 Gene

Price¹,

Greaves

Watkins³

2001

Journal of Biological Chemistry

375

313

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Matrix metalloproteinase-2 (MMP-2) is an enzyme with proteolytic activity against matrix and nonmatrix proteins, particularly basement membrane constituents. Thus, any naturally occurring genetic variants that directly affect gene expression and/or protein function would be expected to impact on progression of pathological processes involving tissue remodeling. We scanned a 2-kilobase pair promoter region and all 13 exons of the human MMP-2 gene, from a panel of 32 individuals, and we identified the position, nature, and relative allele frequencies of 15 variant loci as follows: 6 in the promoter, 1 in the 5-untranslated region, 6 in the coding region, 1 in intronic sequence, and 1 in the 3-untranslated region. The majority of coding region polymorphisms resulted in synonymous substitutions, whereas three promoter variants (at ؊1306, ؊790, and ؉220) mapped onto cis-acting elements. We functionally characterized all promoter variants by transient transfection experiments with 293, RAW264.7, and A10 cells. The common C 3 T transition at ؊1306 (allele frequency 0.26), which disrupts an Sp1-type promoter site (CCACC box), displayed a strikingly lower promoter activity with the T allele. Electrophoretic mobility shift assays confirmed that these differences in allelic expression were attributable to abolition of Sp1 binding. These data suggest that this common functional genetic variant influences MMP-2 gene transcription in an allele-specific manner and is therefore an important candidate to test for association in a wide spectrum of pathologies for which a role for MMP-2 is implicated, including atherogenesis and tumor invasion and metastasis.

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Section: Discussionmentioning

confidence: 99%

Identification of Novel, Functional Genetic Variants in the Human Matrix Metalloproteinase-2 Gene

Price¹,

Greaves

Watkins³

2001

Journal of Biological Chemistry

375

313

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show abstract

“…While we have not conclusively demonstrated that Areg, Ereg, Btc, or Il6 gene expression is regulated by NF-kB p65 or p52, several studies have demonstrated that Il6 gene expression is positively regulated by p65 (Kang et al 1996, Chen et al 2008, Ndlovu et al 2009). Conversely, our data suggest that decreased phosphorylation of p65 and/or increased processing of p52 may directly or indirectly contribute to the synergistic effects of cAMP and IGF1 on Il6 mRNA abundance.…”

Section: Discussionmentioning

confidence: 55%

cAMP-dependent regulation of ovulatory response genes is amplified by IGF1 due to synergistic effects on Akt phosphorylation and NF-κB transcription factors

et al. 2012

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Granulosa cells play a crucial role as mediator of the LH-dependent ovulatory response. The intraovarian factor IGF1 is produced by ovarian somatic cells of healthy follicles during the ovulatory response. The objective of this study was to identify mechanisms by which IGF1, alone or in combination with LH, regulates the expression of genes in granulosa cells, which are crucial for ovulation. To achieve this objective, short-term, primary murine granulosa cell cultures were treated for 2-8 h with 1 mM 8-bromoadenosine 3 0 ,5 0 -cAMP to mimic the LH surge and/or 100 ng/ml IGF1. While cAMP induced significant increases in the expression of important ovulatory response genes including amphiregulin (Areg), epiregulin (Ereg), betacellulin (Btc), or interleukin 6 (Il6), IGF1 alone had no effect. However, co-treatment of cells with IGF1 and cAMP had a synergistic effect on Areg, Ereg, Btc, and Il6 mRNA abundance. Pretreatment of granulosa cells with the MEK1/2 inhibitor U0126 demonstrated that cAMP-dependent increases in Areg, Ereg, Btc, and Il6 were mediated by extracellular regulated kinase 1/2 phosphorylation. However, western blot analyses coupled with pretreatment of cells with the PI3K inhibitor LY294002 indicated that the synergistic effect of cAMP and IGF1 on transcript levels was due in part to cooperative increases in Akt phosphorylation. Western blot analyses also demonstrated that IGF1 and the combined treatment of cAMP and IGF1 decreased NF-kB p65 phosphorylation and increased NF-kB p52 levels. Together, these data indicate that IGF1 may amplify cAMP-dependent regulation of ovulatory response gene expression above an important threshold level and therefore represents a novel role for IGF1 during ovulation.

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“…2B), which is also produced by macrophages on activation [38]. It has been previously shown that BALB/c3T3 can produce a high amount of IL-6 after LPS (1 µg/mL) treatment [39]. Thus, Fig.…”

Section: Discussionmentioning

confidence: 78%

“…First, in the experiments reported here, LPS and IFN-␥ have been washed away before target cells were added to the culture, resulting in little being present to activate IL-6 production by 3T3-VSV. Second, the level of LPS used to activate the macrophages was 100 times less than that used by Kang et al [39] even before the macrophages were washed. Third, the levels of IL-6 in our negative control groups, including unactivated macrophages with either target cell, were always below detectable limits (1.25 units/mL).…”

Section: Discussionmentioning

confidence: 94%

Interaction with vesicular stomatitis virus-infected BALB/c3T3 cells inhibits the synthesis of nitric oxide in activated murine bone marrow culture-derived macrophages

Crowder

Murphy

Russell

et al. 1999

Journal of Leukocyte Biology

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Binding and Functional Effects of Transcriptional Factor Sp1 on the Murine Interleukin-6 Promotor

Cited by 45 publications

References 53 publications

Identification of Novel, Functional Genetic Variants in the Human Matrix Metalloproteinase-2 Gene

Identification of Novel, Functional Genetic Variants in the Human Matrix Metalloproteinase-2 Gene

cAMP-dependent regulation of ovulatory response genes is amplified by IGF1 due to synergistic effects on Akt phosphorylation and NF-κB transcription factors

Interaction with vesicular stomatitis virus-infected BALB/c3T3 cells inhibits the synthesis of nitric oxide in activated murine bone marrow culture-derived macrophages

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