A lymphoid-specific protein binding to the octamer motif of immunoglobulin genes

Staudt, Louis M.; Singh, Harinder; Sen, Ranjan; Wirth, Thomas; Sharp, Phillip A.; Baltimore, David

doi:10.1038/323640a0

Cited by 704 publications

(511 citation statements)

References 24 publications

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“…The binding pattern may be complicated by differential occupancy of binding sites, by posttranslational modifications of some nuclear factors, or by the binding of distinct factors with similar binding specificities to the same DNA site. Indeed, the latter situation has been observed for several nuclear factor binding sites (1,10,13,(15)(16)(17). The apparent ability of different regions of the promoter to bind to the same nuclear factor, or to factors with similar binding specificities (e.g., the sequences 5' and 3' of + 11), is reminiscent of the SV40 early promoter, which contains multiple Spl binding sites.…”

Section: Resultsmentioning

confidence: 99%

Localization of transcriptional regulatory elements and nuclear factor binding sites in mouse ribosomal protein gene rpL32.

Atchison¹,

Meyuhas²,

Perry³

1989

Mol. Cell. Biol.

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The DNA sequences required for expression of the ribosomal protein gene rpL32 were identified by transient-expression assays of chimeric rpL32-chloramphenicol acetyltransferase genes. These studies showed that maximal rpL32 expression requires sequences in a 150-to 200-base-pair region spanning the transcriptional start site. Three discrete regions of importance were identified: one between positions -79 and -69 and two others located downstream of the transcriptional start site. Progressive 5' or 3' deletions caused stepwise decreases in expression, which suggested a complex interplay of redundant or compensatory elements. Gel mobility shift assays were used to idenfify trans-acting nuclear factors which bind to segments of the rpL32 promoter that are known to be important for transcription. Evidence for several distinct nuclear factors is presented. The binding sites for these factors were localized to the following regions: -79 to -69, -36 to -19, -19 to +11, +11 to +46 in exon I, and within the first 31 base pairs of intron 1. One of these factors may bind to multiple sites within the promoter region. Interestingly, the factor that binds to a sequence motif in the first exon also binds to similar motifs in a comparable region of the c-myc gene.The ribosomal proteins are structurally diverse and evolutionarily unrelated to each other, yet the genes that encode them are expressed with very similar efficiencies, as indicated by the relatively uniform abundance of various ribosomal protein mRNAs and by the similar RNA polymerase loading of different ribosomal protein genes (11, 12; D. E. Kelley and R. P. Perry, unpublished observations). What is the basis for this similarity? Presumably, the transcriptional efficiency of a ribosomal protein gene should ultimately be determined by the characteristics of its particular set of regulatory elements and by the cellular content of transacting factors that interact with these elements. To improve our understanding of these elements and factors, we have sought to define the DNA sequences that constitute the complete promoter of the ribosomal protein gene rpL32 and to identify the nuclear factors that bind to the functionally important sequences. Using a series of constructs in which selected portions of the rpL32 promoter region were linked to a chloramphenicol acetyltransferase (CAT) reporter gene, we observed that maximal expression requires sequences in a 150-to 200-base-pair (bp) region spanning the transcriptional start site, including sequences within exon I and intron 1. Moreover, we show that there are several discrete nuclear factor binding sites within this region, at least one of which recognizes a factor that is also bound by the myc gene promoter. These findings, together with previous and other parallel studies of rpL32 expression (2, 5; R. Moura-Neto, K. P. Dudov, and R. P. Perry, Proc. Natl. Acad. Sci. USA, in press), have delineated the complex set of sequences that determine the efficiency of rpL32 transcription. The unusual organization of this promote...

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Section: Resultsmentioning

confidence: 99%

Localization of transcriptional regulatory elements and nuclear factor binding sites in mouse ribosomal protein gene rpL32.

Atchison¹,

Meyuhas²,

Perry³

1989

Mol. Cell. Biol.

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“…Studies on the expression of OCT.1 have demonstrated a high-level expression in pre-B cell lines. 12,13 On the other hand, OCT.2 expression is restricted to B cells and neuronal cells, 14 and plays an important role in Ig promoter transactivation, as has been demonstrated by transfection experiments. 15 They both participate in the control of important B-specific genes involved in proliferation and differentiation, [16][17][18][19][20] such as Ig genes, CD20, CD79a and J chain.…”

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confidence: 84%

Analysis of transcription factor OCT.1, OCT.2 and BOB.1 expression using tissue arrays in classical Hodgkin's lymphoma

et al. 2004

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Hodgkin's lymphoma can be considered in most cases a B-cell lymphoma due to the presence of potentially functional immunoglobulin (Ig) gene rearrangements in the neoplastic cells. In contrast to lymphocytepredominant Hodgkin's lymphoma, Hodgkin/Reed-Sternberg (HRS) cells from classical Hodgkin's lymphoma have low frequency of B-cell marker expression and lack Ig light and Ig heavy messenger RNA. Recent studies have shown transcription machinery deficiency in Hodgkin's lymphoma caused by an absence of the transcription factors OCT.1, OCT.2 and/or BOB.1. By using the tissue microarray technique, we have performed an immunohistochemical study of OCT.1, OCT.2 and BOB.1 in 325 classical Hodgkin's lymphoma cases. The results have been correlated with the expression of the B-cell markers CD20, CD79a, B-cell-specific activator protein (BSAP) and MUM.1, the presence of Epstein-Barr virus and the histological subtype. The percentage of CD20 and CD79a positivity was low (18 and 18%, respectively), whereas MUM.1 and BSAP were positive in the majority of cases. Considering the positive cases with independence of the intensity of staining, 62% of them expressed OCT.2, 59% OCT.1 and 37% BOB.1. Nevertheless, when we considered only the strongly positive cases, the results were similar to those previously described by others. No statistical association was found between the transcription factor expression, histological subtype and Epstein-Barr virus presence. To our knowledge, this is the largest series of classical Hodgkin's lymphoma cases in which the expression of transcription factors has been studied. We have found a notorious percentage of cases displaying weak positivity for OCT.2 and BOB.1 factors in HRS cells. We propose that other mechanisms different from the absence of transcription factors OCT.2 and BOB.1 might be involved in the control of Ig transcription and B lineage in classical Hodgkin's lymphoma.

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“…In addition, the inducible accessibility of the intron enhancer as measured by DNase I hypersensitivity (38) may represent some of the earliest events involved in providing accessibility of the locus to the V(D)J recombinase. There are also a number of inducible transcription factors that bind to the intron enhancer or adjacent sequences, including AP-1, Oct-2, KBF-A, and NF-B (30,41,47,52). It has also been shown previously that the intron enhancer is capable of targeting recombination of substrates in transgenic mice (15,20).…”

Section: Discussionmentioning

confidence: 99%

Coordinate Transcription and V(D)J Recombination of the Kappa Immunoglobulin Light-Chain Locus: NF-κB-Dependent and -Independent Pathways of Activation

O'Brien

Oltz

Ness

1997

Molecular and Cellular Biology

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To further elucidate the potential role of mitogens and cytokines in regulation of the kappa immunoglobulin light-chain locus, we have characterized the activation of transcription factor binding, kappa germ line transcription, DNase I hypersensitivity, and V -to-J recombination upon induction of model pre-B-cell lines. We find that both lipopolysaccharide (LPS) and gamma interferon (IFN-␥) are capable of activating germ line transcription, DNase I hypersensitivity, and recombination of the kappa locus. We also find that transforming growth factor ␤ is capable of completely inhibiting LPS activation of transcription and recombination but has no apparent effect on activation of transcription factor binding, It is becoming increasingly clear that the tissue-specific and developmentally regulated transcription and recombination of immunoglobulin (Ig) gene segments represent overlapping points of control during B-cell development. The concomitant activation of transcription and recombination of all Ig loci has led to the suggestion that transcription of unrearranged Ig genes plays a key role in regulating recombination (23, 31, 37, 44-46, 55, 60, 61). A number of observations have provided strong support for this hypothesis. First, while a common V(D)J recombinase is expressed in both B cells and T cells, functional recombination of Ig genes is restricted to B cells, where they are also transcriptionally active (62). While ectopic expression of the recombinase activating genes RAG-1 and RAG-2 has been shown to confer V(D)J recombinase activity to integrated and extrachromosomal substrates in nonlymphoid cells, the endogenous Ig loci, which are transcriptionally silent in these cells, do not undergo recombination (19,25,33). In addition, it has been demonstrated previously that induction of germ line transcription of the unrearranged kappa Ig lightchain and heavy-chain loci is accompanied by an increased frequency of gene rearrangement (44, 45). More direct evidence that cis-acting transcriptional regulatory elements are involved in recombination has been demonstrated by integration of recombination substrates by using transfection approaches (5, 6, 11, 24, 35), transgenic approaches (15-17, 20, 21), and targeted knockouts of endogenous sequences (18,48,54,59).While there is strong evidence that cis-acting transcriptional regulatory regions within the kappa Ig light-chain locus play a role in recombination, the mechanism by which they regulate recombination and the trans-acting factors involved have yet to be elucidated. The observation that cells are able to regulate the ability of the endogenous kappa locus to serve as a substrate for the V(D)J recombinase has led to the suggestion that transcription may target the locus by providing accessibility of the locus to the recombinase (see reviews in references 32, 39, and 47). The mechanism by which transcription may mediate accessibility is not clear; however, changes in local chromatin structure within the kappa locus have been shown to occur upon transcriptional ac...

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A lymphoid-specific protein binding to the octamer motif of immunoglobulin genes

Cited by 704 publications

References 24 publications

Localization of transcriptional regulatory elements and nuclear factor binding sites in mouse ribosomal protein gene rpL32.

Localization of transcriptional regulatory elements and nuclear factor binding sites in mouse ribosomal protein gene rpL32.

Analysis of transcription factor OCT.1, OCT.2 and BOB.1 expression using tissue arrays in classical Hodgkin's lymphoma

Coordinate Transcription and V(D)J Recombination of the Kappa Immunoglobulin Light-Chain Locus: NF-κB-Dependent and -Independent Pathways of Activation

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