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Blood, Vol. 93 No. 11 (June 1), 1999:
pp. 3900-3912
Posttranslational Regulation of Myc Function in Response to Phorbol
Ester/Interferon- -Induced Differentiation of v-Myc-Transformed
U-937 Monoblasts
Fuad Bahram,
Siqin Wu,
Fredrik Öberg,
Bernhard Lüscher, and
Lars-Gunnar Larsson
From the Department of Genetics and Pathology, University of Uppsala,
University Hospital, Uppsala, Sweden; and the Institut für
Molekularbiologie, Medizinische Hochschule Hannover, Carl-Neuberg
Strasse 1, Hannover, Germany.
The transcription factors of the Myc/Max/Mad network are important
regulators of cell growth, differentiation, and apoptosis and are
frequently involved in tumor development. Constitutive expression of
v-Myc blocks phorbol ester (TPA)-induced differentiation of human U-937 monoblasts. However, costimulation with interferon- (IFN-) and TPA restores terminal differentiation and G1
cell-cycle arrest despite continuous expression of v-Myc. The mechanism
by which TPA + IFN- counteract v-Myc activity has not been
unravelled. Our results show that TPA + IFN- treatment led to an
inhibition of v-Myc- and c-Myc-dependent transcription, and a
specific reduction of v-Myc:Max complexes and associated DNA-binding
activity, whereas the steady state level of the v-Myc protein was only
marginally affected. In contrast, TPA + IFN- costimulation neither
increased the expression of Mad1 or other mad/mnt family genes
nor altered heterodimerization or DNA-binding activity of Mad1. The
reduced amount of v-Myc:Max heterodimers in response to treatment was accompanied by partial dephosphorylation of v-Myc and c-Myc.
Phosphatase treatment of Myc:Max complexes lead to their dissociation,
thus mimicking the effect of TPA + IFN-. In addition to modulation of the expression of Myc/Max/Mad network proteins, posttranslational negative regulation of Myc by external signals may, therefore, be an
alternative biologically important level of control with potential
therapeutic relevance for hematopoietic and other tumors with
deregulated Myc expression.
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