let‐7‐repressesed <scp>S</scp>hc translation delays replicative senescence

Xu, Fang; Pang, Lihua; Cai, Xiaoyu; Liu, Xinwen; Yuan, Shuai; Fan, Xiuqin; Jiang, Bin; Zhang, Xiaowei; Dou, Yali; Gorospe, Myriam; Wang, Wengong

doi:10.1111/acel.12176

Cited by 20 publications

(29 citation statements)

References 31 publications

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“…Repression of Shc has been associated with delaying replicative senescence in fibroblasts. (24) In our case, because of the effect on steatosis, it was tempting to speculate that the Shc/NOX2 axis is potentially involved in Sirt1 dysregulation. To support this notion, we found that Sirt1 was reduced during aging, and this was reversed by inhibition of Shc in old mice.…”

Section: Figmentioning

confidence: 74%

Nonphagocytic Activation of NOX2 Is Implicated in Progressive Nonalcoholic Steatohepatitis During Aging

et al. 2020

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BaCKgRoUND aND aIMS: Older patients with obesity/ type II diabetes mellitus frequently present with advanced NASH. Whether this is due to specific molecular pathways that accelerate fibrosis during aging is unknown. Activation of the Src homology 2 domain-containing collagen-related (Shc) proteins and redox stress have been recognized in aging; however, their link to NASH has not been explored. appRoaCH aND ReSUltS: Shc expression increased in livers of older patients with NASH, as assessed by real time quantitative PCR (RT-qPCR) or western blots. Fibrosis, Shc expression, markers of senescence, and nicotinamide adenine dinucleotide phosphate, reduced form oxidases (NOXs) were studied in young/old mice on fast food diet (FFD). To inhibit Shc in old mice, lentiviral (LV)-short hairpin Shc versus control-LV were used during FFD. For hepatocyte-specific effects, floxed (fl/fl) Shc mice on FFD were injected with adeno-associated virus 8-thyroxine-binding globulin-Cre-recombinase versus control. Fibrosis was accelerated in older mice on FFD, and Shc inhibition by LV in older mice or hepatocyte-specific deletion resulted in significantly improved inflammation, reduction in senescence markers in older mice, lipid peroxidation, and fibrosis. To study NOX2 activation, the interaction of p47 phox (NOX2 regulatory subunit) and p52Shc was evaluated by proximity ligation and coimmunoprecipitations. Palmitate-induced p52Shc binding to p47 phox , activating the NOX2 complex, more so at an older age. Kinetics of binding were assessed in Src homology 2 domain (SH2) or phosphotyrosine-binding (PTB) domain deletion mutants by biolayer interferometry, revealing the role of SH2 and the PTB domains. Lastly, an in silico model of p52Shc/p47 phox interaction using RosettaDock was generated. CoNClUSIoNS: Accelerated fibrosis in the aged is modulated by p52Shc/NOX2. We show a pathway for direct activation of the phagocytic NOX2 in hepatocytes by p52Shc binding and activating the p47 phox subunit that results in redox stress and accelerated fibrosis in the aged. (Hepatology 2020;72:1204-1218). N ASH and associated cirrhosis are the leading causes of liver-related mortality in the United States and worldwide. (1) The incidence of NASH rises strikingly with age, contributing significantly to elder mortality. (2) Older patients are often excluded from liver transplantation because of comorbidities and the age limit for transplantation; therefore, a significant increase in NASH-related mortality is expected because NASH has no approved medical treatment. Most of the preclinical data in NASH/fibrosis research is derived from experiments employing young mice. In clinical trials, however, the target population is usually middle-aged or elderly. To

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Section: Figmentioning

confidence: 74%

Nonphagocytic Activation of NOX2 Is Implicated in Progressive Nonalcoholic Steatohepatitis During Aging

et al. 2020

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“…All plasmids were transfected using lipofectamine 2000 (Invitrogen) and collected 48 to 72 h after transfection for further analysis. SA-β-galactosidase activity (β-gal staining) was performed as described previously [42]. …”

Section: Methodsmentioning

confidence: 99%

NSun2 delays replicative senescence by repressing p27 (KIP1) translation and elevating CDK1 translation

Tang

Fan

Xing

et al. 2015

Aging

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100

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A rise in the levels of the cyclin-dependent kinase (CDK) inhibitor p27KIP1 is important for the growth arrest of senescent cells, but the mechanisms responsible for this increase are poorly understood. Here, we show that the tRNA methyltransferase NSun2 represses the expression of p27 in replicative senescence. NSun2 methylated the 5′-untranslated region (UTR) of p27 mRNA at cytosine C64 in vitro and in cells, thereby repressing the translation of p27. During replicative senescence, increased p27 protein levels were accompanied by decreased NSun2 protein levels. Knockdown of NSun2 in human diploid fibroblasts (HDFs) elevated p27 levels and reduced the expression of CDK1 (encoded by CDK1 mRNA, a previously reported target of NSun2), which in turn further repressed cell proliferation and accelerated replicative senescence, while overexpression of NSun2 exerted the opposite effect. Ectopic overexpression of the p27 5′UTR fragment rescued the effect of NSun2 overexpression in lowering p27, increasing CDK1, promoting cell proliferation, and delaying replicative senescence. Our findings indicate that NSun2-mediated mRNA methylation regulates p27 and CDK1 levels during replicative senescence.

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“…The elevation in SHC levels through NSUN2 further increased cellular ROS levels, in turn activating p38MAPK, a downstream effector of SHC. [27][28][29] In sum, by targeting different mRNAs, NSUN2 exerts opposite effects in the processes of replicative senescence and stress-induced premature senescence.…”

Section: Nsun2 In Cell Senescencementioning

confidence: 98%

“…Although the increase in NSUN2 in HUVEC (human umbilical vein endothelial cell) exposed to oxidants and high glucose did not accompany a rise in the levels of CDK1 or CDC25C, it did lead to a rise in the production of the senescence‐regulatory factors TP53, SHC, and p16 (Figure ). The elevation in SHC levels through NSUN2 further increased cellular ROS levels, in turn activating p38MAPK, a downstream effector of SHC . In sum, by targeting different mRNAs, NSUN2 exerts opposite effects in the processes of replicative senescence and stress‐induced premature senescence.…”

Section: Nsun2 In Cell Senescencementioning

confidence: 99%

“…25 By activating the p38 mitogen-activated protein kinase (MAPK) and elevating cellular ROS levels, SHC proteins shorten animal longevity, reduce cellular lifespan, and accelerate replicative senescence. [27][28][29] Although the increase in NSUN2 in HUVEC (human umbilical vein endothelial cell) exposed to oxidants and high glucose did not accompany a rise in the levels of CDK1 or CDC25C, 26 it did lead to a rise in the production of the senescence-regulatory factors TP53, SHC, and p16 ( Figure 2). The elevation in SHC levels through NSUN2 further increased cellular ROS levels, in turn activating p38MAPK, a downstream effector of SHC.…”

Section: Nsun2 In Cell Senescencementioning

confidence: 99%

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mRNA methylation by NSUN2 in cell proliferation

Wang

2016

WIREs RNA

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Methylation is a prevalent post-transcriptional modification that occurs in almost all RNA species. NSUN2, a nucleolar RNA methyltransferase, has been shown to methylate mRNAs encoding factors that control cell division and growth arrest, thereby affecting their stability and/or translation. Here, the author summarizes the recent progress in understanding NSUN2-mediated mRNA methylation and its implications in cell proliferation and senescence. WIREs RNA 2016, 7:838-842. doi: 10.1002/wrna.1380 For further resources related to this article, please visit the WIREs website.

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let‐7‐repressesed Shc translation delays replicative senescence

Cited by 20 publications

References 31 publications

Nonphagocytic Activation of NOX2 Is Implicated in Progressive Nonalcoholic Steatohepatitis During Aging

Nonphagocytic Activation of NOX2 Is Implicated in Progressive Nonalcoholic Steatohepatitis During Aging

NSun2 delays replicative senescence by repressing p27 (KIP1) translation and elevating CDK1 translation

mRNA methylation by NSUN2 in cell proliferation

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