Increased Oxidative Metabolism in the Li–Fraumeni Syndrome

Wang, Ping Yuan; Ma, Wenzhe; Park, Joon‐Young; Celi, Francesco S.; Arena, Ross; Choi, Jeong Won; Ali, Qais Abu; Tripodi, Dotti; Zhuang, Jie; Lago, Cory U.; Strong, Louise C.; Talagala, S. Lalith; Balaban, Robert S.; Kang, Ju Gyeong; Hwang, Paul M.

doi:10.1056/nejmoa1214091

Cited by 112 publications

(107 citation statements)

References 24 publications

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“…We previously reported that LFS family members who carried TP53 mutations have increased oxidative metabolism (7). These findings were confirmed in a mouse model of LFS that demonstrated the distinction between p53 null and p53 mutant states in regulating the mitochondria (8,9).…”

Section: Introductionmentioning

confidence: 55%

Inhibiting mitochondrial respiration prevents cancer in a mouse model of Li-Fraumeni syndrome

Wang¹,

Li²,

Walcott³

et al. 2016

Journal of Clinical Investigation

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Section: Introductionmentioning

confidence: 55%

Inhibiting mitochondrial respiration prevents cancer in a mouse model of Li-Fraumeni syndrome

Wang¹,

Li²,

Walcott³

et al. 2016

Journal of Clinical Investigation

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“…Compromised exercise capacity in p53-null mice and the effect of mutated p53 on skeletal muscle oxidative metabolism in a human translational study have underscored the importance of this tumor suppressor in exercise physiology (13,17,18,24). A number of studies have explored the effects of exercise on p53.…”

Section: Discussionmentioning

confidence: 99%

Forkhead Box O3A (FOXO3) and the Mitochondrial Disulfide Relay Carrier (CHCHD4) Regulate p53 Protein Nuclear Activity in Response to Exercise

Zhuang

Kamp

et al. 2016

Journal of Biological Chemistry

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Edited by Linda SpremulliAlthough exercise is linked with improved health, the specific molecular mechanisms underlying its various benefits require further clarification. Here we report that exercise increases the nuclear localization and activity of p53 by acutely down-regulating coiled-coil-helix-coiled-coil-helix domain 4 (CHCHD4), a carrier protein that mediates p53 import into the mitochondria. This response to exercise is lost in transgenic mice with constitutive expression of CHCHD4. Mechanistically, exerciseinduced nuclear transcription factor FOXO3 binds to the CHCHD4 promoter and represses its expression, preventing the translocation of p53 to the mitochondria and thereby increasing p53 nuclear localization. The synergistic increase in nuclear p53 and FOXO3 by exercise can facilitate their known interaction in transactivating Sirtuin 1 (SIRT1), a NAD ؉ -dependent histone deacetylase that mediates adaptation to various stresses. Thus, our results reveal one mechanism by which exercise could be involved in preventing cancer and potentially other diseases associated with aging.The nuclear transcriptional activities of p53, well established to play a critical role in tumor suppression, are dynamically regulated by multiple factors, including posttranslational modifications and protein-protein interactions (1-3). Accumulating evidence also shows that p53 localization in non-nuclear subcellular compartments, such as the cytosol and mitochondria, can regulate cellular processes like autophagy and metabolism (4 -6). Although stress-mediated p53 translocation to the mitochondria and its role in cell death have been well delineated, the effect of p53 translocation into mitochondria under normal states is less clear (7,8). Thus, understanding the regulation of p53 partitioning into the mitochondria under physiologic conditions may provide new insights into its tumor-suppressive functions.We reported previously that CHCHD4, 2 the mammalian homolog of the yeast mitochondrial disulfide relay system carrier Mia40, interacts with p53 and mediates its translocation into mitochondria (9). Unlike other mechanisms by which proteins can be imported into mitochondria, the disulfide relay system is coupled to respiration, perhaps reflecting a homeostatic mechanism by which the import of p53 can be regulated by mitochondrial activity (10, 11). Subsequently, p53 import into mitochondria by CHCHD4 facilitates the repair of oxidative mtDNA damage, complementing the nuclear role of p53 in regulating mitochondrial respiration (9, 12, 13). However, these observations also raise questions regarding the physiological significance of the partitioning of p53 between the nucleus and mitochondria and whether such a mechanism can be demonstrated in vivo under normal conditions.Exercise elicits many complex physiological responses, including the induction of specific transcription factors such as PGC-1␣ and peroxisome proliferator-activated receptors, which transactivate mitochondrial biogenesis genes (14, 15). As a mitochondrial protein ...

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“…TP53 also directly stimulates mitochondrial oxidative phosphorylation through transcriptional activation of the gene-encoding synthesis of cytochrome c oxidase 2 (Sco2) (Matoba et al 2006). Interestingly, dysregulated oxidative phosphorylation has been observed in cells from patients with Li -Fraumeni syndrome, which is attributed partly to altered Sco-2 expression (Wang et al 2013).…”

Section: Tumor-suppressor Functions Of Tp53 Pathwaymentioning

confidence: 99%

Tumor-Suppressor Functions of the TP53 Pathway

Aubrey

Strasser

Kelly

2016

Cold Spring Harb Perspect Med

231

157

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The fundamental biological importance of the Tp53 gene family is highlighted by its evolutionary conservation for more than one billion years dating back to the earliest multicellular organisms. The TP53 protein provides essential functions in the cellular response to diverse stresses and safeguards maintenance of genomic integrity, and this is manifest in its critical role in tumor suppression. The importance of Tp53 in tumor prevention is exemplified in human cancer where it is the most frequently detected genetic alteration. This is confirmed in animal models, in which a defective Tp53 gene leads inexorably to cancer development, whereas reinstatement of TP53 function results in regression of established tumors that had been initiated by loss of TP53. Remarkably, despite extensive investigation, the specific mechanisms by which TP53 acts as a tumor suppressor are yet to be fully defined. We review the history and current standing of efforts to understand these mechanisms and how they complement each other in tumor suppression.T he TP53 protein is a critical tumor suppressor that plays a fundamental and multifaceted role in the development of cancer and cancer therapy. Despite more than 30 years of vigorous research and an expansive body of literature, the precise molecular mechanism underlying TP53's tumor-suppressor function has not been defined and remains the focus of active investigation. Understanding the tumorsuppressor function of the Tp53 gene will not only have profound importance to the understanding of cancer biology but will likely have an impact on cancer therapy and prevention through improved exploitation of wild-type Tp53 functions as well as gained insight into specific vulnerabilities imposed on tumors by loss of TP53 function. The TP53 protein exerts effector functions that impact on virtually all of the hallmark features of cancer (Hanahan and Weinberg 2011); however, it is still not clear which of these functions is essential to its potent tumor-suppressor function and how these functions interact. Indeed, it is becoming increasingly apparent that multiple pathways are likely to collaborate in exerting this tumor-suppression function and that the TP53 protein has context-specific roles. Here we discuss the functioning of the TP53 protein as a tumor suppresEditors:

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Increased Oxidative Metabolism in the Li–Fraumeni Syndrome

Cited by 112 publications

References 24 publications

Inhibiting mitochondrial respiration prevents cancer in a mouse model of Li-Fraumeni syndrome

Inhibiting mitochondrial respiration prevents cancer in a mouse model of Li-Fraumeni syndrome

Forkhead Box O3A (FOXO3) and the Mitochondrial Disulfide Relay Carrier (CHCHD4) Regulate p53 Protein Nuclear Activity in Response to Exercise

Tumor-Suppressor Functions of the TP53 Pathway

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