Specific requirement for Bax, not Bak, in Myc-induced apoptosis and tumor suppression in vivo.
ABSTRACT Bax and Bak comprise the mitochondrial gateway for apoptosis induced by diverse stimuli. Loss of both bax and bak is necessary to block cell death induced by such stimuli, indicating a great degree of functional overlap between Bax and Bak. Apoptosis is the major intrinsic pathway that limits the oncogenic potential of Myc. Using a switchable mouse model of Myc-induced apoptosis in pancreatic beta cells, we have shown that Myc induces apoptosis in vivo exclusively through Bax but not Bak. Furthermore, blockade of Myc-induced apoptosis by the inactivation of Bax, but not Bak, eliminates all restraints to the oncogenic potential of Myc, allowing the rapid and synchronous progression of invasive, angiogenic tumors.
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ABSTRACT: p53 is a pivotal tumor suppressor that induces apoptosis, cell-cycle arrest and senescence in response to stress signals. Although p53 transcriptional activation is important for these responses, the mechanisms underlying tumor suppression have been elusive. To date, no single or compound mouse knockout of specific p53 target genes has recapitulated the dramatic tumor predisposition that characterizes p53-null mice. Recently, however, analysis of knock-in mice expressing p53 transactivation domain mutants has revealed a group of primarily novel direct p53 target genes that may mediate tumor suppression in vivo. We present here an overview of well-known p53 target genes and the tumor phenotypes of the cognate knockout mice, and address the recent identification of new p53 transcriptional targets and how they enhance our understanding of p53 transcriptional networks central for tumor suppression.Trends in cell biology 12/2011; 22(2):97-106. · 12.12 Impact Factor
Article: Finding cancer's weakest link.[show abstract] [hide abstract]
ABSTRACT: The biological programs of vertebrates exhibit a remarkable degree of functional degeneracy, adaptive compensation and robustness, to preserve homeostasis and generate reproducible phenotypic outputs irrespective of variations in signal strength, noise and quality. Cancers are difficult to treat not only because they are so mechanistically diverse but also because they adapt or evolve in response to any pharmacological elective pressure we impose upon them. Hence, an ideal cancer drug target would exert a function both necessary for cancer cell survival and functionally non-redundant, rendering it impossible for tumor cells to compensate for, or evolve independence from, the inhibitory effect of any drug aimed at that target. In this review, we discuss the unique, non-degenerate and highly pleiotropic role played by Myc in coordinating, engaging and maintaining the diverse intracellular and extracellular programs required for cell proliferation in vivo. These properties make Myc a compelling candidate cancer drug target, at least in principle: an assertion recently reinforced by new in vivo genetic data.Oncotarget 12/2011; 2(12):1307-13. · 6.64 Impact Factor
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ABSTRACT: Oncogenic transcription factor Myc deregulates the cell cycle and simultaneously reprograms cellular metabolism to meet the biosynthetic and bioenergetic needs of proliferation. Myc also sensitizes cells to mitochondria-dependent apoptosis. Although metabolic reprogramming has been circumstantially connected to vulnerability to apoptosis, the connecting molecular pathways have remained poorly defined. Here, we show that Myc-induced altered glutamine metabolism involves ATP depletion and activation of the energy sensor AMP-activated protein kinase (AMPK), which induces stabilizing phosphorylation of p53 at Ser15. Under influence of Myc, AMPK-stabilized tumor suppressor protein p53 accumulates in the mitochondria and interacts with the protein complex comprised of B-cell lymphoma 2 (Bcl-2) antagonist/killer (BAK) and Bcl2-like 1 (Bcl-xL). Mitochondrial p53 induces conformational activation of proapoptotic Bak without disrupting the Bak-Bcl-xL interaction. Further liberation of Bak specifically from the p53-activated Bak-Bcl-xL complex leads to spontaneous oligomerization of Bak and apoptosis. Thus, Myc-induced metabolic changes are coupled via AMPK and phospho-p53 to the mitochondrial apoptosis effector Bak, demonstrating a cell-intrinsic mechanism to counteract uncontrolled proliferation.Proceedings of the National Academy of Sciences 04/2013; · 9.74 Impact Factor