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J. Biol. Chem., Vol. 276, Issue 11, 8460-8468, March 16, 2001
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From the Department of Biochemistry, MCP Hahnemann University
School of Medicine, Philadelphia, Pennsylvania 19102
Signal transduction by the antigen
receptor complexes is critical for developmental progression of
B-lymphocytes, which are defined by assembly and sequential expression
of immunoglobulin genes, which in turn are regulated by the enhancer
elements. Although proximal antigen-receptor signal transduction
pathways are well defined, the precise nuclear factors targeted by
these signals remained unknown. Previous studies have demonstrated that
tissue-restricted transcription factors including PU.1 and PU. 1 interaction partner (PIP) function synergistically with c-Fos
plus c-Jun to stimulate the
AKT Induces Transcriptional Activity of PU.1 through
Phosphorylation-mediated Modifications within Its Transactivation
Domain*
E3'-enhancer in 3T3 cells. In this
study, we demonstrate that the functional synergy between these factors
is enhanced in response to mitogen-activated protein kinase
kinase kinase, in 3T3 cells, where the enhancer is inactive.
However in S194 plasmacytoma cells, mitogen-activated protein kinase
kinase kinase was able to stimulate the activity of PU.1 but unable to
induce the E3'-enhancer activity. We have found that
Ras-phosphoinositide 3-kinase-dependent externally regulated
kinase, AKT, induces E3'-enhancer activity in both pre-B and
plasmacytoma cells. AKT stimulation of the E3'-enhancer is primarily
due to PU.1 induction and is independent of PU.1 interaction with PIP.
Activation of AKT had no effect on the expression levels of PU.1 or its
protein-protein interaction with PIP. Using a series of deletion
constructs, we have determined that the PU.1 acid-rich (amino acids
33-74) transactivation domain is necessary for AKT-mediated induction.
Substitution analyses within this region indicate that phosphorylation
of Ser41 is necessary to respond to AKT. Consistent
with these studies, ligation of antigen receptors in A20 B cells mimics
AKT activation of PU.1. Taken together, these results provide evidence
that PU.1 is induced by AKT signal in a phosphoinositide
3-kinase-dependent manner, leading to inducible or constitutive
activation of its target genes.
*
This work was supported by National Institutes of Health
Grant AI 46308 (to J. M. R. P.).The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Biochemistry,
School of Medicine, MCP Hahnemann University, 245 N. 15th St.,
Philadelphia, PA 19102. E-mail:
jagan.pongubala@drexel.edu.
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