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Reports
BH3 activation blocks Hdmx suppression of apoptosis and cooperates with Nutlin to induce cell death
Mark Wade, Luo Wei Rodewald, Joaquín M. Espinosa and Geoffrey M. Wahl
volume 7 | issue 13
1 July 2008Subscribe to this journal for $129/year
The Hdmx protein restricts p53 activity in vivo and is overexpressed in a significant fraction of human tumors that retain the wild type p53 allele. An understanding of how Hdmx limits p53 activation and blocks apoptosis could therefore lead to development of novel therapeutic agents. We previously showed that Hdmx modulates tumor cell sensitivity to Nutlin-3a, a potent antagonist of the p53/Hdm2 interaction. In this report, we demonstrate that this also applies to MI-219, another Hdm2 antagonist. Thus, the inability to disrupt Hdmx/p53 complexes is a potential barrier to the efficacy of these compounds as single agents. We show that sensitivity to apoptosis in cells with high Hdmx levels is restored by combined treatment with Hdm2 and a Bcl-2 family member antagonist to activate Bax. The data are consistent with a model in which Hdmx attenuates p53-dependent activation of the intrinsic apoptotic pathway, and that this occurs upstream of Bax activation. Thus, selectively inhibiting Hdm2 and activating Bax is one effective strategy to induce apoptosis in tumors with high Hdmx levels. Our findings also indicate that preferential induction of apoptosis in tumor versus normal cells occurs using appropriate drug doses.
Authors
Mark Wade
Salk Institute for Biological Studies; La Jolla, CA
Luo Wei Rodewald
Salk Institute for Biological Studies; La Jolla, CA
Joaquín M. Espinosa
University of Colorado at Boulder; Boulder, CO
Geoffrey M. Wahl
Salk Institute for Biological Studies; La Jolla, CA