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B-Mediated Signaling
Department of Microbiology and Immunology (G.L., L.-y.Y.-L.), Medicine (L.-y.Y.-L.), and Molecular and Cellular Biology (L.-y.Y.-L.) Baylor College of Medicine Houston, Texas 77030
Signal transducers and activators of
transcription (Stat) are latent transcription factors that participate
in cytokine signaling by regulating the expression of early response
genes. Our previous studies showed that Stat5 functions not only as a
transcriptional activator but also as a transcriptional inhibitor,
depending on the target promoter. This report further investigates the
mechanism of Stat5b-mediated inhibition and demonstrates that
PRL-inducible Stat5b inhibits nuclear factor
B (NFB) signaling to
both the interferon regulatory factor-1 promoter and to the
thymidine kinase promoter containing multimerized NFB elements
(NFB-TK). Further, PRL-inducible Stat5b inhibits tumor necrosis
factor-
signaling presumably by inhibiting endogenous NFB. This
Stat5b-mediated inhibitory effect on NFB signaling is independent of
Stat5b-DNA interactions but requires the carboxyl terminus of Stat5b as
well as Stat5b nuclear translocation and/or accumulation, suggesting
that Stat5b is competing for a nuclear factor(s) necessary for
NFB-mediated activation of target promoters. Increasing
concentrations of the coactivator p300/CBP reverses Stat5b inhibition
at both the interferon-regulatory factor-1 and NFB-TK promoters,
suggesting that Stat5b may be squelching limiting coactivators via
protein-protein interactions as one mechanism of promoter inhibition.
These results further substantiate our observation that Stat factors
can function as transcriptional inhibitors. Our studies reveal
cross-talk between the Stat5b and NFB signal transduction pathways
and suggest that Stat5b-mediated inhibition of target promoters
occurs at the level of protein-protein interactions and involves
competition for limiting coactivators.
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