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1
Department of Pathology and Kaplan Cancer Center, New York University School of Medicine, New York, NY 10016
Lymphocytes derived from mice deficient in STAT1 showed reduced
apoptosis and enhanced proliferation in vitro. To understand the
involvement of STAT1 in the observed reduction in apoptosis, we
examined the levels of caspase and bcl-2 family genes that are involved
in cell survival and/or apoptosis. The levels of caspase 1 and 11, two
enzymes involved in both cytokine protein processing and induction of
apoptosis, were reduced in STAT1-/- cells compared with
wild-type. However, the levels of bcl-2 genes were comparable in both
mice. STAT1-/- cells also displayed an enhanced
proliferation following TCR stimulation. This hyperproliferation could
not be ascribed completely to the loss of IFN-
-mediated
antiproliferation. First, similar phenotypes were also observed in
fibroblasts and pre-B cells derived from STAT1-/- mice,
which do not produce IFN-. Second, comparisons with cells lacking
the gene for IFN- or with cells treated with neutralizing Abs to
IFN- only partially mimicked the STAT1-/- phenotype.
Interestingly, the kinetics of degradation of p27kip1, a
CDK inhibitor, following TCR ligation were faster, and, concomitantly,
the up-regulation of CDK2 kinase activity and protein levels were
increased in stimulated T cells of STAT1-/- mice relative
to those of wild-type mice. Furthermore, STAT1-/- animals
were more susceptible to carcinogen-induced thymic tumors, a possible
consequence of altered T cell growth and/or survival. These results
demonstrate an essential role for STAT1 for lymphocyte survival and
proliferation that is only partially dependent on IFN-
signaling.
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