p53 coordinates decidual sestrin 2/AMPK/mTORC1 signaling to govern parturition timing

Deng, Wenbo; Cha, Jeeyeon; Yuan, Jia; Haraguchi, Hirofumi; Bartos, Amanda; Leishman, Emma; Viollet, Benoı̂t; Bradshaw, Heather B.; Hirota, Yasushi; Dey, Sudhansu K.

doi:10.1172/jci87715

Cited by 65 publications

(53 citation statements)

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“…Recently, SESN2 was reported to be upregulated by UVB, but also by UVA, in melanocytes [42]. Our knockdown experiments in fibroblasts demonstrated that UVB-induced upregulation of SESN2 depends on p53, which is compatible with the presence of a functional p53 binding sites in the promoter and the first intron of SESN2 [43, 44]. Of note, SESN2 has been reported to be under additional regulation by the stress response regulators Nrf2 and JNK in various cell types [12, 45].…”

Section: Discussionsupporting

confidence: 72%

The Expression of the Endogenous mTORC1 Inhibitor Sestrin 2 Is Induced by UVB and Balanced with the Expression Level of Sestrin 1

Mlitz

Gendronneau²,

Berlin³

et al. 2016

PLoS ONE

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Sestrin 2 (SESN2) is an evolutionarily conserved regulator of mechanistic target of rapamycin complex 1 (mTORC1) which controls central cellular processes such as protein translation and autophagy. Previous studies have suggested that SESN2 itself is subjected to regulation at multiple levels. Here, we investigated the expression of SESN2 in the skin and in isolated skin cells. SESN2 was detected by immunofluorescence analysis in fibroblasts and keratinocytes of human skin. Differentiation of epidermal keratinocytes was not associated with altered SESN2 expression and siRNA-mediated knockdown of SESN2 did not impair stratum corneum formation in vitro. However, SESN2 was increased in both cell types when the expression of its paralog SESN1 was blocked by siRNA-mediated knock down, indicating a compensatory mechanism for the control of expression. Irradiation with UVB but not with UVA significantly increased SESN2 expression in both keratinocytes and fibroblasts. Upregulation of SESN2 expression could be completely blocked by suppression of p53. These results suggest that SESN2 is dispensable for normal epidermal keratinization but involved in the UVB stress response of skin cells.

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Section: Discussionsupporting

confidence: 72%

The Expression of the Endogenous mTORC1 Inhibitor Sestrin 2 Is Induced by UVB and Balanced with the Expression Level of Sestrin 1

Mlitz

Gendronneau²,

Berlin³

et al. 2016

PLoS ONE

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“…The TP53 pathway is a central regulator in the process of cellular senescence 1, 2 and the uterine deletion of the Trp53 gene induces spontaneous preterm labor 13, 25, 26, 61 . Since TP53 was down-regulated in the chorioamniotic membranes from women who underwent spontaneous preterm labor or spontaneous labor at term, we next evaluated whether the protein concentration and immunoreactivity of TP53 was different among the study groups.…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, enhanced SA-β-gal activity is a common marker of cellular senescence in both human 33, 62 and murine 13, 25, 37, 61, 62 placental tissues. We determined the SA-β-gal activity in the chorioamniotic membranes from women who underwent spontaneous preterm labor or spontaneous labor at term (Figure 4A).…”

Section: Resultsmentioning

confidence: 99%

Preterm labor in the absence of acute histologic chorioamnionitis is characterized by cellular senescence of the chorioamniotic membranes

Gomez‐Lopez

Romero

Plazyo

et al. 2017

American Journal of Obstetrics and Gynecology

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Background Decidual senescence has been considered a mechanism of disease for spontaneous preterm labor in the absence of severe acute inflammation. Yet, signs of cellular senescence have also been observed in the chorioamniotic membranes from women who underwent the physiological process of labor at term. Objective We aimed to investigate whether, in the absence of acute histologic chorioamnionitis, the chorioamniotic membranes from women who underwent spontaneous preterm labor or labor at term exhibit markers of cellular senescence. Study Design Chorioamniotic membrane samples were collected from women who underwent spontaneous preterm labor or labor at term. Gestational age-matched non-labor controls were also included. Senescence-associated genes/proteins were determined using reverse transcription quantitative polymerase chain reaction analysis (n=7–9 each for array; n= 26–28 each for validation), enzyme-linked immunosorbent assays (n=7–9 each), immunoblotting (n=6–7 each) and immunohistochemistry (n=7–8 each). Senescence-associated β-galactosidase activity (n=7–11 each) and telomere length (n=15–22 each) were also evaluated. Results In the chorioamniotic membranes without acute histologic chorioamnionitis: 1) the expression profile of senescence-associated genes was different between the labor groups (term in labor and preterm in labor) and the non-labor groups (term no labor and preterm no labor); yet, there were differences between the term in labor and preterm in labor groups; 2) most of the differentially expressed genes among the groups were closely related to the tumor suppressor protein 53 (TP53) pathway; 3) the expression of TP53 was down-regulated in the term in labor and preterm in labor groups compared to their non-labor counterparts; 4) the expression of CDKN1A (gene coding for p21) was up-regulated in the term in labor and preterm in labor groups compared to their non-labor counterparts; 5) the expression of the cyclin kinase CDK2 and cyclins CCNA2, CCNB1 and CCNE1 was down-regulated in the preterm in labor group compared to the preterm no labor group; 6) the concentration of TP53 was lower in the preterm in labor group than in the preterm no labor and term in labor groups; 7) the senescence-associated β-galactosidase activity was greater in the preterm in labor group than in the preterm no labor and term in labor groups; 8) the concentration of phospho-S6 ribosomal protein was reduced in the term in labor group compared to its non-labor counterpart but no differences were observed between the preterm in labor and preterm no labor groups, and 9) no significant differences were observed in relative telomere length among the study groups (term no labor, term in labor, preterm no labor, and preterm in labor). Conclusion In the absence of acute histologic chorioamnionitis, signs of cellular senescence are present in the chorioamniotic membranes from women who underwent spontaneous preterm labor compared to those who delivered preterm in the absence of labor. However, the chorioamniotic me...

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“…Currently, several studies have documented that Rev possesses various biological properties, including antioxidant, anti-inflammatory, and anti-proliferative properties, and promotes cell differentiation and apoptosis [27-30]. The data from a recent study showed that Rev reversed the remodelling of the pulmonary vasculature by restoring atrophic gene expression in MCT-induced PH [18].…”

Section: Discussionmentioning

confidence: 99%

Resveratrol Protects Against Pulmonary Arterial Hypertension in Rats via Activation of Silent Information Regulator 1

Jia

et al. 2017

Cell Physiol Biochem

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Background/Objectives: The polyphenol resveratrol (Rev) has been found to exhibit various beneficial effects including prevention of pulmonary arterial hypertension (PAH). The present study was designed to investigate the action and potential mechanism of Rev on PAH, focusing on the role of SIRT1 (Silent Information Regulator 1) in apoptosis of pulmonary artery smooth muscle cells (PASMCs). Methods: PAH rats were established by exposure to hypoxia for 21 days. Rev and SRT1720 (a selective SIRT1 activator) were used to reverse PAH by gavaging rats. PASMCs were confronted with hypoxia for 24 h or 48 h and were then treated with Rev or SRT1720 in vitro. Western blot was performed to detect the protein expression of SIRT1. CCK-8 and scratch wound experiments were carried out to verify cell proliferation. In addition, the TUNEL positive assay and flow cytometry assay were used to measure PASMC apoptosis. Mitochondrial permeability transition (mPT) was identified by confocal microscopy. Right ventricular systolic pressure (RVSP) was determined with a Gould pressure transducer, and right ventricular hypertrophy (RVH) was determined by weighing the cardiac muscle. Results: We demonstrated that Rev could reverse the remodelling of the pulmonary vasculature, thus contributing to alleviating the severity of PAH. Down-regulation of SIRT1 was observed in PAH, but administration of Rev had no obvious effect on the protein expression of SIRT1. In addition, Rev could induce mitochondrial swelling and nuclear pyknosis, leading to small, dense, and dysmorphic mitochondria in rats exposed to hypoxia alone. Rev treatment inhibited PASMC proliferation in a dose-dependent manner in vitro. Incubation with SRT1720, a specific activator of SIRT1, significantly retarded PASMC proliferation and promoted PASMC apoptosis in vitro. The mechanism could be associated with inducing mPT damage in PASMCs. Rev and SRT1720 treatment mitigated RVSP and reduced RVH. Conclusion: Rev produced a beneficial effect partially by enhancing the activation of SIRT1, thus improving RVSP and reducing RVH. SIRT1 activation increased PASMC apoptosis by inducing mPT dysfunction, which might be a novel future strategy for the treatment of PAH.

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p53 coordinates decidual sestrin 2/AMPK/mTORC1 signaling to govern parturition timing

Cited by 65 publications

References 63 publications

The Expression of the Endogenous mTORC1 Inhibitor Sestrin 2 Is Induced by UVB and Balanced with the Expression Level of Sestrin 1

The Expression of the Endogenous mTORC1 Inhibitor Sestrin 2 Is Induced by UVB and Balanced with the Expression Level of Sestrin 1

Preterm labor in the absence of acute histologic chorioamnionitis is characterized by cellular senescence of the chorioamniotic membranes

Resveratrol Protects Against Pulmonary Arterial Hypertension in Rats via Activation of Silent Information Regulator 1

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