INDEPENDENT PATHWAYS FOR DE-REPRESSION OF THE MOUSE IG HEAVY-CHAIN GERM-LINE-EPSILON PROMOTER - AN IL-4 NAF NF-IL-4 SITE AS A CONTEXT-DEPENDENT NEGATIVE ELEMENT/
Dz. Wang et al., INDEPENDENT PATHWAYS FOR DE-REPRESSION OF THE MOUSE IG HEAVY-CHAIN GERM-LINE-EPSILON PROMOTER - AN IL-4 NAF NF-IL-4 SITE AS A CONTEXT-DEPENDENT NEGATIVE ELEMENT/, International immunology, 8(7), 1996, pp. 977-989
The activation of germ-line promoters in the Ig heavy chain loci is re
gulated by cytokines as part of the regulation of B cell commitment to
production of new antibody isotypes. Activation of the germ-line prom
oter of the epsilon heavy chain locus (G epsilon) and production of Ig
E are induced by IL-4 and each is virtually undetectable in the absenc
e of IL-4 or the homologous cytokine IL-13. Basal expression of the G
epsilon promoter is repressed by the non-histone chromosomal protein H
MG-I(Y), which also contributes to promoter inducibility, and IL-4 sti
mulates phosphorylation of the C-terminus of HMG-I(Y) through a rapamy
cin-sensitive pathway. IL-4 treatment of mouse B cells also induces a
G epsilon DNA binding activity with the properties of IL-4 NAF, which
is rapidly induced and requires phosphotyrosine for DNA binding activi
ty. 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 re
pression of basal transcription of the GE 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 pat
hways diverge from the IL-4 receptor and suggest that normal expressio
n of G epsilon RNA or IgE is low in part because the germ-line promote
r is kept in a state of repression which requires de-repression throug
h several cooperative pathways. These pathways target conserved nucleo
tide sequence motifs whose precise function depends on the promoter co
ntext in which they are situated.