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Molecular and Cellular Biology, July 2000, p. 4724-4735, Vol. 20, No. 13
Oregon Cancer Center, Department of Medicine
(Division of Hematology and Medical Oncology) and Department of
Molecular and Medical Genetics, Oregon Health Sciences
University,1 and Molecular
Hematopoiesis Laboratory, VA Medical Center,2
Portland, Oregon 97201
Received 14 September 1999/Returned for modification 24 February
2000/Accepted 7 April 2000
Hematopoietic progenitor cells from Fanconi anemia (FA) group C
(FA-C) patients display hypersensitivity to the apoptotic effects of
gamma interferon (IFN-
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
The Fanconi Anemia Protein FANCC Binds to and
Facilitates the Activation of STAT1 by Gamma Interferon and
Hematopoietic Growth Factors
) and constitutively express a variety of
IFN-dependent genes. Paradoxically, however, STAT1 activation is
suppressed in IFN-stimulated FA cells, an abnormality corrected by
transduction of normal FANCC cDNA. We therefore sought to define
the specific role of FANCC protein in signal transduction through
receptors that activate STAT1. Expression and phosphorylation of
IFN-
receptor
chain (IFN-
R
) and JAK1 and JAK2 tyrosine kinases were equivalent in both normal and FA-C cells. However, in
coimmunoprecipitation experiments STAT1 did not dock at the IFN-
R of
FA-C cells, an abnormality corrected by transduction of the FANCC
gene. In addition, glutathione S-transferase fusion genes
encoding normal FANCC but not a mutant FANCC bearing an inactivating point mutation (L554P) bound to STAT1 in lysates of
IFN-
-stimulated B cells and IFN-, granulocyte-macrophage
colony-stimulating factor- and stem cell factor-stimulated MO7e cells.
Kinetic studies revealed that the initial binding of FANCC was to
nonphosphorylated STAT1 but that subsequently the complex moved to the
receptor docking site, at which point STAT1 became phosphorylated. The STAT1 phosphorylation defect in FA-C cells was functionally significant in that IFN induction of IFN response factor 1 was suppressed and
STAT1-DNA complexes were not detected in nuclear extracts of FA-C
cells. We also determined that the IFN-
hypersensitivity of FA-C
hematopoietic progenitor cells does not derive from STAT1 activation
defects because granulocyte-macrophage CFU and erythroid burst-forming
units from STAT1
/
mice were resistant to IFN-
.
However, BFU-E responses to SCF and erythropoietin were suppressed in
STAT
/
mice. Consequently, because the FANCC protein
is involved in the activation of STAT1 through receptors for at least
three hematopoietic growth and survival factor molecules, we reason
that FA-C hematopoietic cells are excessively apoptotic because of an
imbalance between survival cues (owing to a failure of STAT1 activation
in FA-C cells) and apoptotic and mitogenic inhibitory cues
(constitutively activated in FA-C cells in a STAT1-independent fashion).
*
Corresponding author. Mailing address: Oregon Cancer
Center, Oregon Health Sciences University, Portland, OR 97201. Phone: (503) 494-6343. Fax: (503) 494-7086. E-mail:
grover{at}ohsu.edu.
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