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J Biol Chem, Vol. 275, Issue 2, 867-874, January 14, 2000
From the Department of Pathology, Yale University School of
Medicine, New Haven, Connecticut 06520
Many cytokines have dual functions of promoting
or inhibiting cell proliferation; however, the molecular mechanism of
the dual functions of cytokines is not well understood. Under normal conditions, interleukin (IL)-3 is required for Ba/F3 cell
proliferation, whereas interferon (IFN)-
Interferon-
Has Dual Potentials in Inhibiting or Promoting
Cell Proliferation*
and
inhibits Ba/F3 cell
proliferation. It is known that Stat1 play a major role in inhibition
of cell growth in response to IFN-. We have examined the possibility of whether IFN- can act as a growth-promoting cytokine if the Stat1
function is selectively blocked. We have established variant Ba/F3 cell
lines in which Stat1 function is inhibited by a dominant-negative Stat1
mutant. Intriguingly, once Stat1 function is inhibited, IFN- can
replace IL-3 acting as an essential growth factor for cell
proliferation. To understand the molecular mechanism of regulation of
cell proliferation by the cytokines, the signaling pathways and gene
induction by IL-3 and IFN- are further studied. Although IL-3
activates mitogenic-activated protein kinase and Akt kinase, IFN-
does not. Interestingly, both IL-3 and IFN- induce expression of the
c-Myc gene that is not dependent on the Stat1 activity. Expression of a
dominant-negative mutant Myc can block IFN--mediated Ba/F3 cell
proliferation, suggesting that c-Myc gene induction is required for
IFN--mediated cell proliferation. These findings suggest that
IFN- intrinsically and simultaneously induces specific and
conflicting signaling pathways and transcriptional programs that
contribute to the potential dual effects of IFN- in promoting or
inhibiting cell proliferation.
*
This work was supported by National Institutes of Health
Grants GM55590 and AI34522 (to X.-Y. F.).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.
Present address: Dept. of Microbiology and Immunology Tohoku
University School of Medicine, Sendai, Japan.
§
Recipient of a Career Development Award from the National
Institutes of Health. To whom correspondence should be addressed: Dept.
of Pathology, Yale University School of Medicine, 310 Cedar St., New
Haven, CT 06520. Tel.: 203-737-1246; Fax: 203-737-1247; E-mail:
xin- yuan.fu{at}yale.edu.
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