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J. Biol. Chem., Vol. 276, Issue 45, 42565-42574, November 9, 2001
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From the Department of Biology, The College of William and Mary,
Williamsburg, Virginia 23187
The Pax-5 gene plays a central role
in B cell development, activation, and differentiation. At least four
different isoforms have been identified, of which isoform Pax-5a has
been extensively studied, while functions for alternative isoforms were
previously unknown. Here, using a transient transfection system, we
provide evidence that alternative isoform Pax-5d acts as a
dominant-negative regulator by suppressing activity of Pax-5a in a
dose-dependent manner. In contrast, co-expression in the
presence of alternative isoform Pax-5e causes an increase in Pax-5a
activity. Protein studies on Pax-5e using Western blot analysis
revealed that this 19-kDa isoform migrates as a 27-kDa species on
SDS-polyacrylamide electrophoresis gels, while a mutant Pax-5e
form in which a C-terminal cysteine residue has been mutated, runs at
the expected 19 kDa. Using both Western blot and immunoprecipitation
assays, we further provide evidence that this size discrepancy may be
caused by a tight association between Pax-5e and a thioredoxin-like
factor. Comparison of various B cell lines as well as resting and
lipopolysaccharide-activated mature B lymphocytes shows that increased
B cell proliferation correlates with increased levels of
Pax-5e/thioredoxin, whereas increased Pax-5d amounts correlate with
inhibition of cell growth. Together, our results suggest that during
activation and differentiation of B lymphocytes, Pax-5a function is
modulated by two alternative spliced isoforms: the dominant negative
Pax-5d isoform may mediate inhibition of Pax-5a activity in resting B
cells, while alternative isoform Pax-5e associated with thioredoxin may
increase Pax-5a activity through an unknown (redox) mechanism.
Functional Analyses of Two Alternative Isoforms of the
Transcription Factor Pax-5*
*
This work was supported by Nationa Science Foundation CAREER
Award MCB-9874795 (to P. Z.).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 Biology, The
College of William and Mary, Williamsburg, VA 23187. Tel.: 757-221-1969; Fax: 757-221-6483; E-mail: pxzwol@wm.edu.
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