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Mol Cell Biol, May 1998, p. 2545-2552, Vol. 18, No. 5
Molecular Oncology Program, H. Lee Moffitt
Cancer Center and Research Institute, and Department of Biochemistry
and Molecular Biology, University of South Florida College of Medicine,
Tampa, Florida 33612,1 and
Department
of Pulmonary Diseases, University Hospital Utrecht,
Heidelberglaan, 3584 CX Utrecht, The Netherlands2
Received 16 September 1997/Returned for modification 13 November
1997/Accepted 30 January 1998
While signal transducers and activators of transcription (STATs)
were originally discovered as intracellular effectors of normal
signaling by cytokines, increasing evidence also points to a role for
STAT transcription factors in oncogenesis. Previous studies have
demonstrated that one STAT family member, Stat3, possesses
constitutively elevated tyrosine phosphorylation and DNA-binding
activity in fibroblasts stably transformed by the Src oncoprotein. To
determine if this Stat3 activation by Src could induce Stat3-mediated
gene expression, luciferase reporter constructs based on synthetic and
authentic promoters were transfected into NIH 3T3 cells. Activation of
endogenous cellular Stat3 by the Src oncoprotein induced gene
expression through a Stat3-specific binding element (TTCCCGAA)
of the C-reactive protein gene promoter. A naturally occurring
splice variant of human Stat3 protein, Stat3
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Stat3 Activation by Src Induces Specific Gene
Regulation and Is Required for Cell Transformation
, with a deletion in the
C-terminal transactivation domain abolished this gene induction in a
dominant negative manner. Expression of Stat3
did not have any
effect on a reporter construct based on the c-fos serum
response element, which is not dependent on Stat3 signaling, indicating
that Stat3
does not nonspecifically inhibit other signaling pathways
or Src function. Transfection of vectors expressing Stat3
together
with Src blocked cell transformation by Src as measured in a
quantitative focus formation assay using NIH 3T3 cells. By contrast,
Stat3
had a much less pronounced effect on focus formation induced
by the Ras oncoprotein, which does not activate Stat3 signaling. In
addition, three independent clones of NIH 3T3 cells stably
overexpressing Stat3
were generated and characterized, demonstrating
that Stat3
overexpression does not have a toxic effect on cell
viability. These Stat3
-overexpressing clones were shown to be
deficient in Stat3-mediated signaling and refractory to Src-induced
cell transformation. We conclude that Stat3 activation by the Src
oncoprotein leads to specific gene regulation and that Stat3 is one of
the critical signaling pathways involved in Src oncogenesis. Our
findings provide evidence that oncogenesis-associated activation of
Stat3 signaling is part of the process of malignant transformation.
*
Corresponding author. Mailing address: Molecular
Oncology Program, Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., Tampa, FL 33612. Phone: (813) 979-6725. Fax: (813)
979-6700. E-mail: richjove{at}moffitt.usf.edu.
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