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J. Biol. Chem., Vol. 275, Issue 51, 40155-40162, December 22, 2000
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From the The typical proliferative response of
hepatocytes to tumor necrosis factor (TNF) can be converted to a
cytotoxic one by transcriptional arrest. Although NF-
Inhibition of c-Myc Expression Sensitizes Hepatocytes to Tumor
Necrosis Factor-induced Apoptosis and Necrosis*
,,,,, and¶
Department of Medicine and Marion Bessin
Liver Research Center, Albert Einstein College of Medicine, Bronx, New
York 10461 and § IDUN Pharmaceuticals, Inc.,
La Jolla, California 92037
B activation is
critical for hepatocyte resistance to TNF toxicity, the contribution of
other TNF-inducible transcription factors remains unknown. To determine
the function of c-Myc in hepatocyte sensitivity to TNF, stable
transfectants of the rat hepatocyte cell line RALA255-10G containing
sense and antisense c-myc expression vectors were isolated
with increased (S-Myc cells) and decreased (AN-Myc cells) c-Myc
transcriptional activity. While S-Myc cells proliferated in response to
TNF treatment, AN-Myc cells underwent 32% cell death within 6 h.
Fluorescent microscopic studies indicated that TNF induced apoptosis
and necrosis in AN-Myc cells. Cell death was associated with DNA
hypoploidy and poly(ADP-ribose) polymerase cleavage but occurred in the
absence of detectable caspase-3, -7, or -8 activation. TNF-induced,
AN-Myc cell death was dependent on Fas-associated protein with death
domain and partially blocked by caspase inhibitors. AN-Myc cells had
decreased levels of NF-B transcriptional activity, but S-Myc cells
maintained resistance to TNF despite NF-B inactivation, suggesting
that c-Myc and NF-B independently mediate TNF resistance. Thus, in the absence of sufficient c-Myc expression, hepatocytes are sensitized to TNF-induced apoptosis and necrosis. These findings demonstrate that
hepatocyte resistance to TNF is regulated by multiple transcriptional activators.
*
This work was supported by National Institutes of Health
Grants DK-44234 (to M. J. C.) and DK-32972 (to R. J. S.), an
Australian National Health and Medical Council Research scholarship (to
B. E. J.), and an American Digestive Health Foundation Astra/Merck Fellowship/Faculty Transition Award (to B. E. J.). The FACS facility is funded in part by National Institutes of Health Grant 5P30-CA13330 (to the Albert Einstein Cancer Center).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.
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