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-Induced ERK1/2 Activation in Kaposi’s Sarcoma Cells1
*
Department of Microbiology and Immunology, University of California, Los Angeles, School of Medicine, Los Angeles, CA 90095; and
Institute of Molecular Medicine, Huntington Memorial Hospital, Pasadena, CA 91105
TNF-
is a key pathogenic mediator of infectious and inflammatory
diseases. HIV infection stimulates and dysregulates the immune system,
leading to abnormal production of TNF-. Despite its cytotoxic effect
on some tumor cell lines, TNF- functions as a growth stimulator for
Kaposi’s sarcoma (KS), a common malignancy in HIV-infected patients.
However, signaling pathways linked to TNF--induced mitogenic
responses are not well understood. We found that extracellular
signal-regulated kinases 1 and 2 (ERK1/2) in KS cells were
significantly activated by TNF- through tyrosine/threonine
phosphorylation. Using neutralizing anti-TNFR-I and TNFR-II mAbs,
we have now obtained evidence that TNF--induced KS cell growth and
ERK1/2 activation are mediated exclusively by TNFR-I, not by TNFR-II. A
selective inhibitor for ERK1/2 activator kinases, PD98059, profoundly
inhibited not only the activation of ERK1/2, but also the
TNF--induced KS cell proliferation. We therefore propose that the
TNFR-I-ERK1/2 pathway plays a pivotal role in transmitting to KS cells
the mitogenic signals of TNF-. TNFR-I possesses no intrinsic kinase
activity, suggesting that TNFR-I-associated proteins may provide a link
between TNFR-I and ERK1/2 activation. We found that actinomycin D
treatment of KS cells selectively abolished expression of
mitogen-activated protein kinase-activating death domain protein
(MADD), a novel TNFR-I-associated death domain protein. TNF- failed
to induce ERK1/2 activation in the actinomycin D-treated cells. MADD
may couple TNFR-I with the ERK1/2 signaling pathway required for KS
cell proliferation.
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