Emerging Non-Canonical Functions and Regulation of p53

Ranjan, Atul; Iwakuma, Tomoo

doi:10.3390/ijms19041015

Cited by 9 publications

(7 citation statements)

References 37 publications

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“…TP53 takes part in several biological processes that include stress response, senescence, cell cycle regulation, insulin homeostasis, and cellular metabolism ( Krstic et al, 2018 ). Owing to a wide range of functions of TP53 , and its emerging role in cellular metabolism ( Ranjan and Iwakuma, 2018 ), it is plausible to hypothesize that p53 duplication could have an adaptive role in elephant metabolism, thermoregulation, and habitat adaptation.…”

Section: Crosstalk Between Adaptation and Lifespan Extensionmentioning

confidence: 99%

Lifespan Extension in Long-Lived Vertebrates Rooted in Ecological Adaptation

Omotoso

Gladyshev

Zhou

2021

Front. Cell Dev. Biol.

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Contemporary studies on aging and longevity have largely overlooked the role that adaptation plays in lifespan variation across species. Emerging evidence indicates that the genetic signals of extended lifespan may be maintained by natural selection, suggesting that longevity could be a product of organismal adaptation. The mechanisms of adaptation in long-lived animals are believed to account for the modification of physiological function. Here, we first review recent progress in comparative biology of long-lived animals, together with the emergence of adaptive genetic factors that control longevity and disease resistance. We then propose that hitchhiking of adaptive genetic changes is the basis for lifespan changes and suggest ways to test this evolutionary model. As individual adaptive or adaptation-linked mutations/substitutions generate specific forms of longevity effects, the cumulative beneficial effect is largely nonrandom and is indirectly favored by natural selection. We consider this concept in light of other proposed theories of aging and integrate these disparate ideas into an adaptive evolutionary model, highlighting strategies in decoding genetic factors of lifespan control.

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Section: Crosstalk Between Adaptation and Lifespan Extensionmentioning

confidence: 99%

Lifespan Extension in Long-Lived Vertebrates Rooted in Ecological Adaptation

Omotoso

Gladyshev

Zhou

2021

Front. Cell Dev. Biol.

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“…There is a plethora of evidence that p53 regulates biological processes like the stress response, cell cycle, proliferation, invasion, senescence, apoptosis, and autophagy; to name only the most important ones [ 2 , 4 ]. In addition, noncanonical functions of p53 in post-mitotic, noncancerous cells have been described more recently [ 5 , 6 , 7 ]. These cancer-unrelated functions of p53 are plausible with respect to the process of evolutionary selection, because cancer is a disease that appears, or becomes life-threatening, mainly after reproductive age.…”

Section: Introductionmentioning

confidence: 99%

p53 Functions in Adipose Tissue Metabolism and Homeostasis

Krstić

Reinisch

Schupp

et al. 2018

IJMS

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As a tumor suppressor and the most frequently mutated gene in cancer, p53 is among the best-described molecules in medical research. As cancer is in most cases an age-related disease, it seems paradoxical that p53 is so strongly conserved from early multicellular organisms to humans. A function not directly related to tumor suppression, such as the regulation of metabolism in nontransformed cells, could explain this selective pressure. While this role of p53 in cellular metabolism is gradually emerging, it is imperative to dissect the tissue- and cell-specific actions of p53 and its downstream signaling pathways. In this review, we focus on studies reporting p53’s impact on adipocyte development, function, and maintenance, as well as the causes and consequences of altered p53 levels in white and brown adipose tissue (AT) with respect to systemic energy homeostasis. While whole body p53 knockout mice gain less weight and fat mass under a high-fat diet owing to increased energy expenditure, modifying p53 expression specifically in adipocytes yields more refined insights: (1) p53 is a negative regulator of in vitro adipogenesis; (2) p53 levels in white AT are increased in diet-induced and genetic obesity mouse models and in obese humans; (3) functionally, elevated p53 in white AT increases senescence and chronic inflammation, aggravating systemic insulin resistance; (4) p53 is not required for normal development of brown AT; and (5) when p53 is activated in brown AT in mice fed a high-fat diet, it increases brown AT temperature and brown AT marker gene expression, thereby contributing to reduced fat mass accumulation. In addition, p53 is increasingly being recognized as crucial player in nutrient sensing pathways. Hence, despite existence of contradictory findings and a varying density of evidence, several functions of p53 in adipocytes and ATs have been emerging, positioning p53 as an essential regulatory hub in ATs. Future studies need to make use of more sophisticated in vivo model systems and should identify an AT-specific set of p53 target genes and downstream pathways upon different (nutrient) challenges to identify novel therapeutic targets to curb metabolic diseases.

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“…Caspase-3 is involved in the pathogenesis of doxorubicin-induced cardiomyopathy [ 59 , 60 ] and nephropathy [ 61 ]. As a more proximal step in the cell response to doxorubicin toxicity, p53 overexpression plays a major role in developing dilatative cardiomyopathy and chronic kidney disease [ 11 ] mainly through its’ genomic integrity monitoring activity [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

18F-FDG PET/MRI Imaging in a Preclinical Rat Model of Cardiorenal Syndrome—An Exploratory Study

Furcea

Agrigoroaie

Mihai

et al. 2022

IJMS

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Cardiorenal syndrome (CRS) denotes the bidirectional interaction of chronic kidney disease and heart failure with an adverse prognosis but with a limited understanding of its pathogenesis. This study correlates biochemical blood markers, histopathological and immunohistochemistry features, and 2-deoxy-2-fluoro-D-glucose positron emission tomography (18F-FDG PET) metabolic data in low-dose doxorubicin-induced heart failure, cardiorenal syndrome, and renocardiac syndrome induced on Wistar male rats. To our knowledge, this is the first study that investigates the underlying mechanisms for CRS progression in rats using 18F-FDG PET. Clinical, metabolic cage monitoring, biochemistry, histopathology, and immunohistochemistry combined with PET/MRI (magnetic resonance imaging) data acquisition at distinct points in the disease progression were employed for this study in order to elucidate the available evidence of organ crosstalk between the heart and kidneys. In our CRS model, we found that chronic treatment with low-dose doxorubicin followed by acute 5/6 nephrectomy incurred the highest mortality among the study groups, while the model for renocardiac syndrome resulted in moderate-to-high mortality. 18F-FDG PET imaging evidenced the doxorubicin cardiotoxicity with vascular alterations, normal kidney development damage, and impaired function. Given the fact that standard clinical markers were insensitive to early renal injury, we believe that the decreasing values of the 18F-FDG PET-derived renal marker across the groups and, compared with their age-matched controls, along with the uniform distribution seen in healthy developing rats, could have a potential diagnostic and prognostic yield in cardiorenal syndrome.

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Emerging Non-Canonical Functions and Regulation of p53

Abstract: The tumor suppressor p53 induces cell cycle arrest and/or apoptosis by transactivating numerous downstream target genes and also translocating to the mitochondrial outer membrane.

Cited by 9 publications

References 37 publications

Lifespan Extension in Long-Lived Vertebrates Rooted in Ecological Adaptation

Lifespan Extension in Long-Lived Vertebrates Rooted in Ecological Adaptation

p53 Functions in Adipose Tissue Metabolism and Homeostasis

18F-FDG PET/MRI Imaging in a Preclinical Rat Model of Cardiorenal Syndrome—An Exploratory Study

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