TY - JOUR
T1 - Independent pathways for de-repression of the mouse Ig heavy chain germ-line ε promoter
T2 - An IL-4 NAF/NF-IL-4 site as a context-dependent negative element
AU - Wang, Ding Zhi
AU - Cherrington, Andrea
AU - Famakin-Mosuro, Bolanle
AU - Boothby, Mark
N1 - Funding Information:
We gratefully acknowledge gifts by J. Stavnezer and F. Melchers of the mlL-4-producmg myeloma transfectant, rapamycin from S Sehgal (Wyeth-Ayerst), and purified recombinant human IL-4 from J deVries (DNAX) and M Widmer (Immunex) We thank G Miller for critically reading the manuscript and helpful discussions, and apologize to researchers where the use of alternative citations led to omission of relevant published work The research reported here was supported by grants from the NIH (GM42550), the Baxter Foundation through its Scholars Program and the Leukemia Society of America, of which M R B. was a Special Fellow.
PY - 1996
Y1 - 1996
N2 - The activation of germ-line promoters in the Ig heavy chain loci is regulated by cytokines as part of the regulation of B cell commitment to production of new antibody isotypes. Activation of the germ-line promoter of the ε heavy chain locus (Gε) and production of IgE are induced by IL-4 and each is virtually undetectable in the absence of IL-4 or the homologous cytokine IL-13. Basal expression of the Gε promoter is repressed by the non-histone chromosomal protein HMG-I(Y), which also contributes to promoter inducibility, and IL-4 stimulates phosphorylation of the C-terminus of HMG-I(Y) through a rapamycin-sensitive pathway. IL-4 treatment of mouse B cells also induces a Gε DNA binding activity with the properties of IL-4 NAF, which is rapidly induced and requires phosphotyrosine for DNA binding activity. This protein binds to a different site from HMG-I(Y), but the IL-4 NAF/NF-IL-4 binding site also is a negative element more active in repression of basal transcription of the Gε promoter. This site acts as a negative element when transferred to the thymidine kinase promoter, but does not confer inducibility. In contrast to HMG-I(Y), IL-4 NAF/NF-IL-4 activation is refractory to rapamycin but sensitive to genistein. These findings indicate that two independent signal transduction pathways diverge from the IL-4 receptor and suggest that normal expression of Gε RNA or IgE is low in part because the germ-line promoter is kept in a state of repression which requires de-repression through several cooperative pathways. These pathways target conserved nucleotide sequence motifs whose precise function depends on the promoter context in which they are situated.
AB - The activation of germ-line promoters in the Ig heavy chain loci is regulated by cytokines as part of the regulation of B cell commitment to production of new antibody isotypes. Activation of the germ-line promoter of the ε heavy chain locus (Gε) and production of IgE are induced by IL-4 and each is virtually undetectable in the absence of IL-4 or the homologous cytokine IL-13. Basal expression of the Gε promoter is repressed by the non-histone chromosomal protein HMG-I(Y), which also contributes to promoter inducibility, and IL-4 stimulates phosphorylation of the C-terminus of HMG-I(Y) through a rapamycin-sensitive pathway. IL-4 treatment of mouse B cells also induces a Gε DNA binding activity with the properties of IL-4 NAF, which is rapidly induced and requires phosphotyrosine for DNA binding activity. This protein binds to a different site from HMG-I(Y), but the IL-4 NAF/NF-IL-4 binding site also is a negative element more active in repression of basal transcription of the Gε promoter. This site acts as a negative element when transferred to the thymidine kinase promoter, but does not confer inducibility. In contrast to HMG-I(Y), IL-4 NAF/NF-IL-4 activation is refractory to rapamycin but sensitive to genistein. These findings indicate that two independent signal transduction pathways diverge from the IL-4 receptor and suggest that normal expression of Gε RNA or IgE is low in part because the germ-line promoter is kept in a state of repression which requires de-repression through several cooperative pathways. These pathways target conserved nucleotide sequence motifs whose precise function depends on the promoter context in which they are situated.
KW - Gene regulation
KW - Germ-line promoter IL-4
KW - IL-4 NAF/NF-IL-4
KW - Repressor
KW - Stat proteins
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U2 - 10.1093/intimm/8.7.977
DO - 10.1093/intimm/8.7.977
M3 - Article
C2 - 8757943
AN - SCOPUS:0030018195
SN - 0953-8178
VL - 8
SP - 977
EP - 989
JO - International Immunology
JF - International Immunology
IS - 7
ER -