Engaging the p53 metabolic brake drives senescence
Emerging evidence suggests that the ability of p53 to regulate me tabolism is important for its tumor suppressor activity. A recent study published in Nature reveals a novel connection between p53 and metabo lism: p53 transcriptionally represses the expression of malic enzymes and associated NADPH p...
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Veröffentlicht in: | Cell research 2013-06, Vol.23 (6), p.739-740 |
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Zusammenfassung: | Emerging evidence suggests that the ability of p53 to regulate me tabolism is important for its tumor suppressor activity. A recent study published in Nature reveals a novel connection between p53 and metabo lism: p53 transcriptionally represses the expression of malic enzymes and associated NADPH production, which in turn triggers a positive feedback loop resulting in sustained p53 activa tion, cellular senescence, and tumor suppression. The p53 tumor suppressor plays a key role in combatting malignant trans formation [1]. p53 is a cellular stress sensor that induces cell cycle arrest, cellular senescence or apoptosis in re sponse to stresses such as DNA damage and oncogenic signals, p53 drives these responses primarily through its ability to regulate networks of downstream target genes. While years of p53 research have focused on elucidating the molecular details of how p53 triggers cell cycle arrest or apoptosis in response to acute DNA damage, it has become clear from recent in vivo studies in mouse models that these responses are dispensable for tumor suppression [23], raising the question of which p53 functions are of paramount importance for suppressing cancer development. Interestingly, in creasing evidence over the past decade has illuminated an active role for p53 in the regulation of cellular metabolism, echoing the recognition of metabolic reprogramming as a new hallmark of cancer [45]. Indeed, a diversity of stud ies has revealed that p53 counteracts cancerassociated metabolic transfor mation at various points in the metabolic network. Underscoring the importanceof this function for tumor suppression, a recent study in mouse models has sug gested that the ability of p53 to regulate metabolism and to promote antioxidant responses is intimately associated with tumor suppression [6]. These observa tions emphasize the critical importance of further elaborating the role of p53 in regulating metabolism and how this contributes to cancer suppression. One of the hallmarks of tumor cells is that they actively engage aerobic gly colysis as a means to generate compo nents for macromolecular synthesis and for NADPH production [7]. NADPH is critical for anabolic metabolism, as it provides reducing equivalents necessary for lipid biosynthesis, and facilitates the production of reduced glutathione, an important antioxidant, to protect tumor cells from reactive oxygen spe cies (ROS)induced damage. Inhibiting NADPH production may therefore represent an effecti |
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ISSN: | 1001-0602 1748-7838 |
DOI: | 10.1038/cr.2013.34 |