Structural features of the human C3 gene: Intron/exon organization, transcriptional start site, and promoter region sequence
Department of Pediatrics, Washington University in St. Louis, San Luis, Missouri, United States Biochemistry
(Impact Factor: 3.02).
02/1991; 30(4):1080-5. DOI: 10.1021/bi00218a029
The third component of human complement (C3) is a key molecule in the activation of the complement cascade. C3 cDNA fragments were used to identify seven cosmid clones that covered all but 1 kilobase pair (kb) of the C3 gene. The remainder of the gene was cloned by using the polymerase chain reaction. These clones were used to identify the intron/exon boundaries and to map the gene. The C3 gene is 42 kb in length and comprises 41 exons ranging in size from 52 to 213 base pairs (bp). The transcription start site was identified by primer extension, and approximately 1 kb of DNA upstream of this site was sequenced. Putative TATA and CAAT boxes were identified along with a number of regions that shared homology with known regulatory sequences. These include responsive elements for interferon-gamma, interleukin-6, nuclear factor kappa B, estrogen, glucocorticoids and thyroid hormone. Several of these agents have been shown to affect C3 synthesis and mRNA levels. The sizes of the exons in C3 were compared to those of C4 and alpha 2-macroglobulin (alpha 2M). Thirty-nine of 41 exons in C4 were found to be of similar size to the analogous ones in C3, and two-thirds of those in alpha 2M were also similarly sized, supporting the hypothesis that these genes arose from a common ancestor.
Available from: Zsolt Liposits
- "In the aging female cortex, we demonstrated down-regulation of C3 in the presence of estrogens. This finding is in line with the presence of 3 ERE sequences in the C3 promoter [57,58] and estrogenic regulation of C3 in other tissues . Up-regulation of early C components has been reported recently in the aging mouse forebrain . "
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ABSTRACT: Estrogens exert anti-inflammatory and neuroprotective effects in the brain mainly via estrogen receptors α (ERα) and β (ERβ). These receptors are members of the nuclear receptor superfamily of ligand-dependent transcription factors. This study was aimed at the elucidation of the effects of ERα and ERβ agonists on the expression of neuroinflammatory genes in the frontal cortex of aging female rats.
To identify estrogen-responsive immunity/inflammation genes, we treated middle-aged, ovariectomized rats with 17β-estradiol (E2), ERα agonist 16α-lactone-estradiol (16α-LE2) and ERβ agonist diarylpropionitrile (DPN), or vehicle by Alzet minipump delivery for 29 days. Then we compared the transcriptomes of the frontal cortex of estrogen-deprived versus ER agonist-treated animals using Affymetrix Rat230 2.0 expression arrays and TaqMan-based quantitative real-time PCR. Microarray and PCR data were evaluated by using Bioconductor packages and the RealTime StatMiner software, respectively.
Microarray analysis revealed the transcriptional regulation of 21 immunity/inflammation genes by 16α-LE2. The subsequent comparative real-time PCR study analyzed the isotype specific effects of ER agonists on neuroinflammatory genes of primarily glial origin. E2 regulated the expression of sixteen genes, including down-regulation of complement C3 and C4b, Ccl2, Tgfb1, macrophage expressed gene Mpeg1, RT1-Aw2, Cx3cr1, Fcgr2b, Cd11b, Tlr4 and Tlr9, and up-regulation of defensin Np4 and RatNP-3b, IgG-2a, Il6 and ER gene Esr1. Similar to E2, both 16α-LE2 and DPN evoked up-regulation of defensins, IgG-2a and Il6, and down-regulation of C3 and its receptor Cd11b, Ccl2, RT1-Aw2 and Fcgr2b.
These findings provide evidence that E2, 16α-LE2 and DPN modulate the expression of neuroinflammatory genes in the frontal cortex of middle-aged female rats via both ERα and ERβ. We propose that ERβ is a promising target to suppress regulatory functions of glial cells in the E2-deprived female brain and in various neuroinflammatory diseases.
Journal of Neuroinflammation 07/2011; 8(1):82. DOI:10.1186/1742-2094-8-82 · 5.41 Impact Factor
Available from: Jeni C A Luckett
- "As far as complement is concerned, the dual role of adipose tissue (metabolism and host defense) is echoed by the dual role complement plays in relation to adipose tissue: on the one hand local complement production provides a constituent of triglyceride synthesis, on the other hand it furnishes a local immune repertoire that can be activated during local and systemic inflammation. This dualism may be mirrored in the gene of the central complement component, C3, an acute phase reactant: The promoter of the C3 gene harbours estrogen-response elements (Vik et al., 1991). While there is no obvious reason why the abundance of the innate immune response should differ between the sexes, the presence of these regulatory elements may indeed more readily connect to sex-related fat metabolism. "
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ABSTRACT: Once thought of as purely the body's chief energy store, adipose tissue and its constituent adipocytes have emerged as both a metabolic entity and an endocrine one. Complement is generally thought of as originating mainly from hepatic synthesis but also from synthesis by the macrophage phagocyte system. This review revisits early descriptions of adipocytic synthesis of complement components and highlights the need of a systematic analysis of the contribution of adipose tissue to systemic inflammation in order to appreciate the immunological activity of this tissue.
Molecular Immunology 11/2008; 46(5):755-60. DOI:10.1016/j.molimm.2008.09.013 · 2.97 Impact Factor
Available from: endocrinology-journals.org
- "www.endocrinology.org gene (Vik et al. 1991). The signal cascades involved are still unknown and may vary for different genes with similar sensitivity to estrogenic compounds. "
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ABSTRACT: Phytohormones and chemical compounds revealing estrogenic effects are of increasing interest for their possible influence on the physiology of the reproductive tract. The gap junction connexin (Cx) genes Cx26 and Cx43, the plasma glycoprotein clusterin gene and the complement C3 gene are highly regulated by estrogen in rat endometrium. To test the value of these genes as markers for estrogenic responsiveness we analyzed the effects of estradiol, diethylstilbestrol, the selective estrogen receptor modulators (SERMs) raloxifene and tamoxifen, the phytoestrogens genistein and daidzein, and the industrial compounds DDT (1,1,1-trichloro-2-(2-chlorophenyl)-2-(4-chlorophenyl) ethane) and polychlorinated biphenyl (PCB) on the transcription of these genes in rat endometrium in vivo. Enhancement of Cx26 and decrease of clusterin transcripts expression by estradiol was observed at 0.03 micro g/250 g body weight (BW), and induction of C3 expression was observed at 0.05 micro g/250 g BW. A comparable effect was obtained by a tenfold higher concentration of diethylstilbestrol. Tamoxifen had a regulatory effect on this set of genes at about a 300-fold higher concentration, while raloxifen revealed much weaker estrogenic activity. No effect on Cx43 transcripts was observed with any of the compounds at the concentrations used. An effect of genistein was observed only on Cx26 expression, while PCB decreased clusterin transcripts. These results show that Cx26, C3 and clusterin reveal a comparable sensitivity to estrogens and SERMs. With respect to the phytoestrogen genistein, however, Cx26 seems to be the most sensitive gene. The analysis of clusters of estrogen-sensitive endometrial genes could help to identify estrogenic substances, assess their potency, and elucidate their mechanism of action.
Journal of Molecular Endocrinology 11/2002; 29(2):239-49. · 3.08 Impact Factor
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