The role of the p53 tumor suppressor in metabolism and diabetes

Kung, Che-Pei; Murphy, Maureen E.

doi:10.1530/joe-16-0324

Cited by 128 publications

(120 citation statements)

References 134 publications

(140 reference statements)

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“…The reappearance of beige adipocytes in WATs conceivably contributed to the improved insulin sensitivity in aged Adipoq-p53iKO mice. However, it is also possible that p53 ablation ameliorates insulin resistance via pathways independent of beige adipocyte formation (58,59). From the perspective of energy homeostasis, the restoration of WAT beiging represents an attractive strategy of clinical significance, in that the augmentation of EE and amelioration of white adipocyte hypertrophy, as observed in this study, may eliminate a rudimentary cause of WAT insulin resistance.…”

Section: Discussionmentioning

confidence: 75%

Transient p53 inhibition sensitizes aged white adipose tissue for beige adipocyte recruitment by blocking mitophagy

Liu

Sun

et al. 2018

The FASEB Journal

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Aging of white adipose tissue (WAT) is associated with reduced insulin sensitivity, which contributes to whole-body glucose intolerance. WAT aging in mice impairs cold-induced beige adipocyte recruitment (beiging), which has been attributed to the senescence of adipose progenitor cells. Tumor suppressor p53 has also been implicated in WAT aging. However, whether p53-related cellular aging in mature white adipocytes is causative of age-impaired WAT beiging remains unknown. It is also unclear whether transient p53 inhibition can rescue WAT beiging. Herein, we report that p53 increased in adipose tissues of 28-wk-old (aged) mice with impaired beiging capability. Cold exposure decreased p53 in beiging WAT of young mice but not in aged mice. In aged mice, inducible p53 ablation in differentiated adipocytes restored cold-induced WAT beiging and augmented whole-body energy expenditure and insulin sensitivity. Transient pharmacological inhibition of p53 led to the same beneficial effects. Mechanistically, cold exposure repressed autophagy in beiging WAT of young mice yet increased autophagy in aged WAT. p53-ablation reduced microtubule-associated protein light chain 3-mediated mitochondria clearance (mitophagy) and hence facilitated the increase of mitochondria during beiging. These findings suggest that p53-induced mitophagy in aged white adipocytes impedes WAT beiging and may be therapeutically targeted to improve insulin sensitivity in aged WAT.-Fu, W., Liu, Y., Sun, C., Yin, H. Transient p53 inhibition sensitizes aged white adipose tissue for beige adipocyte recruitment by blocking mitophagy.

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Section: Discussionmentioning

confidence: 75%

Transient p53 inhibition sensitizes aged white adipose tissue for beige adipocyte recruitment by blocking mitophagy

Liu

Sun

et al. 2018

The FASEB Journal

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“…In an old study from 1979, they found that patients with diabetes have two to four times greater risk of developing coronary heart disease (Kannel and McGee, 1979). A literature review by Kung and Murphy (2016) on the role of p53 in metabolism, pancreatic function, glucose homeostasis and insulin resistance showed that p53 is a key player in diabetes and in the severity of diabetic phenotypes. A study conducted on a Russian population concluded that the codon 72 polymorphism of the p53 gene is associated with type 1 diabetes (Spitsina et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…The p53 gene encodes the synthesis of a nuclear phosphoprotein of 53 kDa, where the name p53 comes from, and the protein has 393 amino acids. The functionally active (wild-type) form of p53 has a tetrameric molecular structure (Kung and Murphy, 2016).…”

Section: Introductionmentioning

confidence: 99%

Research Article Analysis of p53 gene polymorphism (codon 72) in symptomatic patients with atherosclerosis.

Lagares¹,

Silva²,

Barbosa³

et al. 2017

Genet. Mol. Res.

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ABSTRACT. Atherosclerosis is a multifactorial pathological disease that alters the morphology and function of arterial walls. The atheroma growth leads to vessel hardening and lumen narrowing, limiting the blood flow. The atheroma plaque can eventually break, expose highly thrombogenic material and lead to platelet activation and subsequent formation of a thrombus that may block blood flow in loco, or even leading to obstruction of other vessels with a smaller diameter. This process is one of the main determinants of the clinical manifestations of atherosclerosis, such as coronary artery disease, ischemic stroke, and peripheral arterial disease. Although the inflammatory theory about atherosclerosis is the most renowned one, observations point to common biological characteristics between cancer and atherosclerosis suggesting a possible association between p53 and atherosclerotic diseases. We collected peripheral blood samples from 200 individuals with clinical manifestations of atherosclerotic disease and 100 individuals without manisfestation of the disease to form the control group. DNA was subjected to molecular analysis (PCR) to identify the polymorphism of the p53 gene. We have not found any relationship between the polymorphism of the p53 gene and atherosclerosis in the population studied (P = 0.36). There was no relationship between atherosclerosis, polymorphism of p53 and the variables accounted: smoking habit (P = 0.72, 0.51 and 0.62 for smokers, non-smokers and former smokers respectively), alcohol consumption (P = 0.17 for individuals with drinking habits and 0.38 for those who do not consume alcohol beverage), systemic arterial hypertension (P = 0.60), diabetes mellitus (P = 0.34), and dyslipidemia (P = 0.89). Our population has a high rate of miscegenation and heterozygotes, and according to studies the arginine variant is more related to plaque formation because it induces apoptosis more frequently when compared to the proline variant. According to our results, there is no association between the polymorphism of the p53 gene, atherosclerosis and its risk factors in the population studied.

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“…2B-E). p53 is also implicated in the development of insulin resistance and diabetes (75). Kyoto Encyclopedia of Genes and Genomes (KEGG; https:// www.genome.jp/kegg/kegg1.html) analysis of the transcriptome of diabetic and nondiabetic mice indicated, in fact, that significant differentially expressed genes closely associate with the p53 signaling network as well as the MAPK and TGF-b pathways (76).…”

Section: Involvement Of P53 In Renal Diseasementioning

confidence: 99%

TGF‐β1–p53 cooperativity regulates a profibrotic genomic program in the kidney: molecular mechanisms and clinical implications

et al. 2019

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Chronic kidney disease affects >15% of the U.S. population and >850 million individuals worldwide. Fibrosis is the common outcome of many chronic renal disorders and, although the etiology varies (i.e., diabetes, hypertension, ischemia, acute injury, and urologic obstructive disorders), persistently elevated renal TGF‐β1 levels result in the relentless progression of fibrotic disease. TGF‐β1 orchestrates the multifaceted program of renal fibrogenesis involving proximal tubular dysfunction, failed epithelial recovery and redifferentiation, and subsequent tubulointerstitial fibrosis, eventually leading to chronic renal disease. Recent findings implicate p53 as a cofactor in the TGF‐β1‐induced signaling pathway and a transcriptional coregulator of several TGF‐β1 profibrotic response genes by complexing with receptor‐activated SMADs, which are homologous to the small worms (SMA) and Drosophilia mothers against decapentaplegic (MAD) gene families. The cooperative p53‐TGF‐β1 genomic cluster includes genes involved in cell growth control and extracellular matrix remodeling [e.g., plasminogen activator inhibitor‐1 (PAI‐1; serine protease inhibitor, clade E, member 1), connective tissue growth factor, and collagen I]. Although the molecular basis for this codependency is unclear, many TGF‐β1‐responsive genes possess p53 binding motifs. p53 up‐regulation and increased p53 phosphorylation; moreover, they are evident in nephrotoxin‐ and ischemia/reperfusion‐induced injury, diabetic nephropathy, ureteral obstructive disease, and kidney allograft rejection. Pharmacologic and genetic approaches that target p53 attenuate expression of the involved genes and mitigate the fibrotic response, confirming a key role for p53 in renal disorders. This review focuses on mechanisms whereby p53 functions as a transcriptional regulator within the TGF‐β1 cluster with an emphasis on the potent fibrosis‐promoting PAI‐1 gene.—Higgins, C. E., Tang, J., Mian, B. M., Higgins, S. P., Gifford, C. C., Conti, D. J., Meldrum, K. K., Samarakoon, R., Higgins, P. J. TGF‐β1‐p53 cooperativity regulates a profibrotic genomic program in the kidney: molecular mechanisms and clinical implications. FASEB J. 33, 10596–10606 (2019). http://www.fasebj.org

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The role of the p53 tumor suppressor in metabolism and diabetes

Cited by 128 publications

References 134 publications

Transient p53 inhibition sensitizes aged white adipose tissue for beige adipocyte recruitment by blocking mitophagy

Transient p53 inhibition sensitizes aged white adipose tissue for beige adipocyte recruitment by blocking mitophagy

Research Article Analysis of p53 gene polymorphism (codon 72) in symptomatic patients with atherosclerosis.

TGF‐β1–p53 cooperativity regulates a profibrotic genomic program in the kidney: molecular mechanisms and clinical implications

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