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Regulation of transcription of the germ-line Ig alpha constant region gene by an ATF element and by novel transforming growth factor-beta 1-responsive elements.
J Immunol. 1992 Nov 01; 149(9):2914-25.JI

Abstract

Inasmuch as transcription of unrearranged, or germ-line, Ig CH genes appears to direct switch recombination, understanding the regulation of this transcription is essential for understanding the regulation of class switching. Transforming growth factor-beta 1 (TGF-beta 1) induces germ-line alpha transcripts and increases class switching to IgA in the I.29 mu B lymphoma and in Peyer's patch and splenic B cells. It has been previously demonstrated that induction of germ-line alpha transcripts by TGF-beta occurs at the transcriptional level in I.29 mu cells. We now demonstrate that the DNA segment located 5' to the initiation sites of germ-line alpha RNA drives expression of a luciferase reporter gene construct in transient transfection experiments. Full constitutive expression requires no more than 106 bp of the 5' flanking segment. By creating a series of deletion and substitution mutations, we have demonstrated that an ATF/CRE site residing within this region is very important for constitutive expression of the germ-line alpha promoter, but mutation of this motif does not diminish TGF-beta induction. Inducibility by TGF-beta requires additional sequences residing between -128 to -106 relative to the first RNA initiation site. Two copies of a tandemly repeated sequence 5' CA-CAG(G)CCAGAC 3' (termed Ig alpha TGF-beta-RE) are located in the region from -127 to -105. An oligonucleotide containing multimers of these repeats confers TGF-beta inducibility to a heterologous promoter. An additional copy of the TGF-beta-RE was identified at -41/-30 and its deletion reduces the TGF-beta response. Thus, we conclude that tandem repeats of a novel TGF-beta-RE are the positive regulatory element for the TGF-beta response. Our study provides further evidence that TGF-beta directs class switching to IgA through induction of transcription of the germ-line C alpha gene and demonstrates that TGF-beta can activate the promoter for the germ-line alpha gene.

Authors+Show Affiliations

Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester 01655.No affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

1401921

Citation

Lin, Y C., and J Stavnezer. "Regulation of Transcription of the Germ-line Ig Alpha Constant Region Gene By an ATF Element and By Novel Transforming Growth Factor-beta 1-responsive Elements." Journal of Immunology (Baltimore, Md. : 1950), vol. 149, no. 9, 1992, pp. 2914-25.
Lin YC, Stavnezer J. Regulation of transcription of the germ-line Ig alpha constant region gene by an ATF element and by novel transforming growth factor-beta 1-responsive elements. J Immunol. 1992;149(9):2914-25.
Lin, Y. C., & Stavnezer, J. (1992). Regulation of transcription of the germ-line Ig alpha constant region gene by an ATF element and by novel transforming growth factor-beta 1-responsive elements. Journal of Immunology (Baltimore, Md. : 1950), 149(9), 2914-25.
Lin YC, Stavnezer J. Regulation of Transcription of the Germ-line Ig Alpha Constant Region Gene By an ATF Element and By Novel Transforming Growth Factor-beta 1-responsive Elements. J Immunol. 1992 Nov 1;149(9):2914-25. PubMed PMID: 1401921.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Regulation of transcription of the germ-line Ig alpha constant region gene by an ATF element and by novel transforming growth factor-beta 1-responsive elements. AU - Lin,Y C, AU - Stavnezer,J, PY - 1992/11/1/pubmed PY - 1992/11/1/medline PY - 1992/11/1/entrez SP - 2914 EP - 25 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J Immunol VL - 149 IS - 9 N2 - Inasmuch as transcription of unrearranged, or germ-line, Ig CH genes appears to direct switch recombination, understanding the regulation of this transcription is essential for understanding the regulation of class switching. Transforming growth factor-beta 1 (TGF-beta 1) induces germ-line alpha transcripts and increases class switching to IgA in the I.29 mu B lymphoma and in Peyer's patch and splenic B cells. It has been previously demonstrated that induction of germ-line alpha transcripts by TGF-beta occurs at the transcriptional level in I.29 mu cells. We now demonstrate that the DNA segment located 5' to the initiation sites of germ-line alpha RNA drives expression of a luciferase reporter gene construct in transient transfection experiments. Full constitutive expression requires no more than 106 bp of the 5' flanking segment. By creating a series of deletion and substitution mutations, we have demonstrated that an ATF/CRE site residing within this region is very important for constitutive expression of the germ-line alpha promoter, but mutation of this motif does not diminish TGF-beta induction. Inducibility by TGF-beta requires additional sequences residing between -128 to -106 relative to the first RNA initiation site. Two copies of a tandemly repeated sequence 5' CA-CAG(G)CCAGAC 3' (termed Ig alpha TGF-beta-RE) are located in the region from -127 to -105. An oligonucleotide containing multimers of these repeats confers TGF-beta inducibility to a heterologous promoter. An additional copy of the TGF-beta-RE was identified at -41/-30 and its deletion reduces the TGF-beta response. Thus, we conclude that tandem repeats of a novel TGF-beta-RE are the positive regulatory element for the TGF-beta response. Our study provides further evidence that TGF-beta directs class switching to IgA through induction of transcription of the germ-line C alpha gene and demonstrates that TGF-beta can activate the promoter for the germ-line alpha gene. SN - 0022-1767 UR - https://www.unboundmedicine.com/medline/citation/1401921/Regulation_of_transcription_of_the_germ_line_Ig_alpha_constant_region_gene_by_an_ATF_element_and_by_novel_transforming_growth_factor_beta_1_responsive_elements_ L2 - https://www.jimmunol.org/lookup/pmidlookup?view=long&pmid=1401921 DB - PRIME DP - Unbound Medicine ER -