Regulation of the immunoglobulin gene transcription

doi:10.1016/0300-9084(90)90167-F

Biochimie

Volume 72, Issue 1, January 1990, Pages 7-17

https://doi.org/10.1016/0300-9084(90)90167-F Get rights and content

Abstract

The transcription of the immunoglobulin heavy (IGH), kappa (IGK) and lambda (IGL) chain genes is coordinate and B lymphocyte specific. This expression of the immunoglobulin genes is under the control of regulatory elements: the promoters located 5′ of each variable (V) gene and the enhancers located between the joining and constant genes in the IGH and IGK locus and downstream on the C kappa gene. These sequences represent sites for the binding of transcription factors. A 90–100 kDA ubiquitous proteins (NF-A1) as well as two specific B cell proteins (NF-A2, OTF-2B) bind to the octamer site of the V promoter and IGH enhancer. The NF-κB protein binds to the κB site in the intron kappa enhancer, but also to κB-like sites found in the promoter regions of other genes. This paper reviews the recent data on these factors and other transcription factors which bind to the promoters and enhancers of the immunoglobulin genes and control their expression.

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Citation Excerpt :
But the mechanism is still to be clearly elucidated. The promoter site of immunoglobulin genes has a binding site for NF-κB [13,14]. As discussed in Section 1, NF-κB plays a major role in T and B lymphocyte functions.
This study explored the effect of hyperthyroid state on humoral immune response and NF-κB signaling in lymphocytes. Male Wistar rats were treated with l-thyroxin for four weeks. Animals were immunized with sheep red blood cells (SRBC) after three weeks of l-thyroxin treatment. After one week of immunization, serum anti-SRBC titer was measured and NF-κB signaling was studied in lymphocytes by Western blot analysis of p-IKB-α, IKB-α, and p65. These results were compared with that of control rats. Antibody response and density of p-IKB-α and p65 were significantly higher in l-thyroxin treated rats in comparison to controls. The antibody response was found to have significant correlation with density of p-IKB-α and p65. Our results indicate that NF-κB signaling pathway in lymphocytes is activated in hyperthyroid state which might play a role in potentiation of antibody response.
An E-box Motif Residing in the Exon/Intron 1 Junction Regulates Both Transcriptional Activation and Splicing of the Human Norepinephrine Transporter Gene
2001, Journal of Biological Chemistry
Citation Excerpt :
This sequence therefore does not belong to the category of classical enhancers, the action of which are independent of position, orientation, or distance in relation to the transcription start site (29). It is increasingly recognized that transcription of some mammalian genes can be influenced by intronic sequences (30-35), and many of them contain important regulatory sequences in the first intron. For example, the first intron (1.8 kb) of the aldolase B gene was shown to be crucial for tissue-specific expression, independent of position and orientation (31).
The norepinephrine transporter (NET) is responsible for the rapid NaCl-dependent uptake of norepinephrine into presynaptic noradrenergic nerve endings. Recently, we have characterized the structural organization of the 5′ upstream promoter region of the human NET (hNET) gene. A new intron of 476 base pairs was found in the middle of the 5′-untranslated leader sequence and was shown to robustly enhance the promoter activity. Here, we show that the first hNET intron enhances both the homologous hNET and the heterologous thymidine kinase promoter activities in an orientation- and position-dependent manner. The first hNET intron exhibited a similar promoter-enhancing effect in both SK-N-BE(2)C (NET-positive) and HeLa (NET-negative) cell lines, showing that its function is not cell-specific. Transient transfection assays of a series of deletional constructs show that the first hNET intron contains subdomains with either positive or negative regulatory functions. Furthermore, DNase I footprinting analysis demonstrated that the 5′ side of the intron, encompassing the splice donor site, is prominently protected by nuclear proteins isolated from both SK-N-BE(2)C and HeLa cells. The protected nucleotide sequence contains a consensus E-box motif, known to regulate diverse eukaryotic genes, which overlaps with the splice donor site of the first intron. We demonstrate that two basic helix-loop-helix proteins, upstream stimulatory factors 1 and 2, are major proteins interacting at this site and that the E-box is at least in part responsible for the promoter-enhancing activity of the first intron. Furthermore, site-directed mutagenesis of the splice donor site of the first intron affects both correct splicing and transcriptional activity. Taken together, our results indicate that acis-element residing at the first exon/intron junction, encompassing an E-box motif, has a unique dual role in basal transcriptional activation and splicing of hNET mRNA.
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2000, Toxicology and Applied Pharmacology
Stress response proteins can play integral roles as modulators of cellular function and can be involved in mechanisms that are important to immune function. Metallothionein (MT), a cysteine-rich stress response protein, has been shown to play numerous roles in the cell: it serves as a reservoir of essential heavy metals, it scavenges free radicals, and it can sequester heavy metals. These various functions suggest that MT may also participate in modulating immune responses. In previous work, we have shown that exogenous metallothionein can suppress the developing humoral immune response when coinjected with antigen. The present study was designed to evaluate the effects of endogenous MT on the development of humoral immunity. We compared the humoral immune function of animals with a targeted disruption of Mt-1 and -2 genes (MTKO) and their wild-type counterparts. MTKO mice displayed a significantly higher humoral response to challenge with ovalbumin (OVA) compared to wild-type controls. The secondary anti-OVA response in MTKO mice is as much as 58% higher than the response in control mice injected at the same time. Overall circulatory immunoglobulin levels are also substantially higher in MTKO mice (0.039 mg/ml IgM and 0.42 mg/ml IgG) than wild-type controls. MTKO mice displayed increased B cell differentiation following OVA challenge and an enhanced lymphoproliferative response to mitogenic stimulation. These changes in immune functional capacity occur in the context of changes in the makeup of the lymphoid compartments of the blood and spleen. There are substantially fewer T and B cells in the circulation of MTKO mice, but more T cells in the spleen of these mice than in control animals. Finally, we have found that splenocytes from MTKO animals displayed significantly elevated levels of NF-κB activity compared to wild-type controls. In conclusion, we have provided evidence that endogenous metallothionein can modulate the immune response in vivo and that intracellular MT may modulate immune function by regulation of transcription factor activity.
An intron facilitates activation of the calspermin gene by the testis-specific transcription factor CREM τ
1995, Journal of Biological Chemistry
Calspermin is a high affinity Ca²⁺/calmodulin binding protein that is found only in postmeiotic male germ cells. Our previous studies have shown that the calspermin transcript is produced by utilization of a testis-specific promoter located within an intron of the calmodulin kinase IV gene. This promoter contains two cAMP response element-like motifs that bind the testis-specific transcription factor CREMτ. This interaction is required for transcriptional activation. Here we describe a novel regulatory element, the 111-base pair first intron of the calspermin gene, which is also required for enhancement of transcription by CREMτ via the cAMP response element motifs. Deletion or inversion of this intron results in loss of CREMτ-mediated stimulation of transcription. However, CREMτ stimulates calspermin promoter activity when the intron is moved upstream of the promoter but only when inserted in the proper orientation. Footprint, linker scanning, and deletion analyses were used to identify regulatory elements in the intron. We suggest that the intron functions as an orientation-dependent but position-independent regulatory element to activate the calspermin promoter by facilitating the stimulatory effect of CREMτ on transcription.
Genomic organisation of 34 kb of the human immunoglobulin lambda locus (IGLV): Restriction map and sequences of new Vλ III genes
1994, Molecular Immunology
In order to improve our knowledge of the human immunoglobulin variable lambda locus (IGLV), we mapped one cosmid clone (designated as C40.2) isolated by screening a Colo320HSR genomic library. The 34 kb insert of the C40.2 clone was shown to contain six genes. One gene, IGLV2S1, belongs to the VλII subgroup. Four genes belong to the VλIII subgroup. Two of them, IGLV3S1 and IGLV3S2, are potentially functional whereas the two others are pseudogenes. The size of the IGLV3S2 leader intron is four times longer than the classical intron size of 110 bp. The cosmid also contains a vestigial sequence λvg2. All these genes share the same orientation of transcription. Pulsed field gel electrophoresis analysis of the IGLV locus shows that most of the Vλ I subgroup genes are located at the 5' end of the locus.

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ReviewRegulation of the immunoglobulin gene transcription

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Regulation of the immunoglobulin gene transcription