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(Received for publication, June 14, 1996, and in revised form, July 2, 1997)
From the Departments of Prolactin (PRL) induces transcriptional
activation of not only growth-related genes such as interferon
regulatory factor-1 (IRF-1) but also differentiation-specific genes
such as
Volume 272, Number 43,
Issue of October 24, 1997
pp. 26841-26849
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
Transcriptional Inhibition by Stat5
DIFFERENTIAL ACTIVITIES AT GROWTH-RELATED VERSUS
DIFFERENTIATION-SPECIFIC PROMOTERS
and§¶
Microbiology and Immunology,
§ Cell Biology, and ¶ Medicine, Baylor College of
Medicine, Houston, Texas 77030
-casein through a signaling cascade consisting of Janus
kinases and Stat (signal transducer and activator of transcription)
factors. To understand better the role of Stats in PRL signaling, we
cloned rat Stat5b from a PRL-responsive T cell line Nb2. A
Stat5b-specific peptide antibody was generated. In PRL receptor
reconstituted COS cells cotransfected with Stat5b or Stat5a, both Stat5
proteins become tyrosine phosphorylated and bind to the IRF-1 GAS
(interferon-
activation sequence) element in a PRL-inducible manner.
Unexpectedly, both Stat5b and Stat5a inhibit PRL induction of the IRF-1
promoter, but they mediate PRL stimulation of the -casein promoter.
Stat5-mediated inhibition was observed only at the native IRF-1
promoter and not at the isolated IRF-1 GAS element linked to a
heterologous thymidine kinase promoter. Mutational analyses showed that
the DNA binding activity of Stat5b is not required, but the
carboxyl-terminal transactivation domain is essential for Stat5b to
inhibit PRL induction of the IRF-1 promoter. These results suggest that
Stat5b mediates inhibition via protein-protein interactions. In
contrast, both DNA binding and transactivation domains of Stat5b are
required to mediate PRL induction of the -casein promoter.
Furthermore, a carboxyl-terminal truncated dominant negative Stat5b can
reverse Stat5b inhibition at the IRF-1 promoter. These studies suggest that Stat proteins can act as not only positive but also negative regulators of gene transcription. Further, Stat5 can modulate gene
expression without binding to DNA but via protein-protein interactions.
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