Lack of Socs2 expression reduces lifespan in high-growth mice

Casellas, J.; Medrano, Juan F.

doi:10.1007/s11357-008-9064-1

Cited by 11 publications

(6 citation statements)

References 31 publications

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“…Such observation supports the notion that IRmediated gene regulation exists in cellular aging models both in vitro and in vivo. Of note, multiple genes with IR changes in our study that were either reported to regulate life span or age-related functions (such as SOCS2 (Casellas & Medrano, 2008) and BAK1 (Someya et al, 2009)) or experimental validated to cause senescence in this study (such as CPNE1) were not presented in the HCSGD database (Dong et al, 2017), suggesting more senescence/aging-associated genes with diverse regulation layers remain to be discovered. We further identified the splicing factor U2AF1 as one of the upstream factors to regulate global intron retention and senescence-associated phenotypes.…”

Section: Discussionmentioning

confidence: 80%

Prevalent intron retention fine‐tunes gene expression and contributes to cellular senescence

Yao

Ding

et al. 2020

Aging Cell

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Intron retention (IR) is the least well‐understood alternative splicing type in animals, and its prevalence and function in physiological and pathological processes have long been underestimated. Cellular senescence contributes to individual aging and age‐related diseases and can also serve as an important cancer prevention mechanism. Dynamic IR events have been observed in senescence models and aged tissues; however, whether and how IR impacts senescence remain unclear. Through analyzing polyA+ RNA‐seq data from human replicative senescence models, we found IR was prevalent and dynamically regulated during senescence and IR changes negatively correlated with expression alteration of corresponding genes. We discovered that knocking down (KD) splicing factor U2AF1, which showed higher binding density to retained introns and decreased expression during senescence, led to senescence‐associated phenotypes and global IR changes. Intriguingly, U2AF1‐KD‐induced IR changes also negatively correlated with gene expression. Furthermore, we demonstrated that U2AF1‐mediated IR of specific gene (CPNE1 as an example) contributed to cellular senescence. Decreased expression of U2AF1, higher IR of CPNE1, and reduced expression of CPNE1 were also discovered in dermal fibroblasts with age. We discovered prevalent IR could fine‐tune gene expression and contribute to senescence‐associated phenotypes, largely extending the biological significance of IR.

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Section: Discussionmentioning

confidence: 80%

Prevalent intron retention fine‐tunes gene expression and contributes to cellular senescence

Yao

Ding

et al. 2020

Aging Cell

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“…In line with a trade-off between immunity and lifespan, administration of a JAK pathway inhibitor reduced inflammation and alleviated cellular senescence [174]. In addition, loss of expression of the JAK/STAT inhibitor Socs2 was associated with decreased lifespan in mice [175]. Opposite to this, the downstream transcription factor STAT3 was found to be protective against inflammation-induced heart damage, highlighting context-dependency of the immuno-ageing properties of JAK/STAT [176].…”

Section: Context-dependent Effects Of the Jak/stat Pathway On Ageing And Immunitymentioning

confidence: 86%

Functional conservation in genes and pathways linking ageing and immunity

et al. 2021

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At first glance, longevity and immunity appear to be different traits that have not much in common except the fact that the immune system promotes survival upon pathogenic infection. Substantial evidence however points to a molecularly intertwined relationship between the immune system and ageing. Although this link is well-known throughout the animal kingdom, its genetic basis is complex and still poorly understood. To address this question, we here provide a compilation of all genes concomitantly known to be involved in immunity and ageing in humans and three well-studied model organisms, the nematode worm Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and the house mouse Mus musculus. By analysing human orthologs among these species, we identified 7 evolutionarily conserved signalling cascades, the insulin/TOR network, three MAPK (ERK, p38, JNK), JAK/STAT, TGF-β, and Nf-κB pathways that act pleiotropically on ageing and immunity. We review current evidence for these pathways linking immunity and lifespan, and their role in the detrimental dysregulation of the immune system with age, known as immunosenescence. We argue that the phenotypic effects of these pathways are often context-dependent and vary, for example, between tissues, sexes, and types of pathogenic infection. Future research therefore needs to explore a higher temporal, spatial and environmental resolution to fully comprehend the connection between ageing and immunity.

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“…Mice lacking SOCS2 exhibit gigantism, thickening dermis, and shortening lifespan ( Casellas and Medrano, 2008 ; Gossing et al, 2021 ). To understand the biological function of SOCS2, SOCS2 –/– mice were generated by deleting a 756-bp fragment in exon 3 through CRISPR/Cas9 technology ( Figure 1A ).…”

Section: Resultsmentioning

confidence: 99%

Suppressor of Cytokine Signaling 2 Regulates Retinal Pigment Epithelium Metabolism by Enhancing Autophagy

Liu

Chen

et al. 2021

Front. Neurosci.

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Retinal pigment epithelium (RPE) serves critical functions in maintaining retinal homeostasis. An important function of RPE is to degrade the photoreceptor outer segment fragments daily to maintain photoreceptor function and longevity throughout life. An impairment of RPE functions such as metabolic regulation leads to the development of age-related macular degeneration (AMD) and inherited retinal degenerative diseases. As substrate recognition subunit of a ubiquitin ligase complex, suppressor of cytokine signaling 2 (SOCS2) specifically binds to the substrates for ubiquitination and negatively regulates growth hormone signaling. Herein, we explore the role of SOCS2 in the metabolic regulation of autophagy in the RPE cells. SOCS2 knockout mice exhibited the irregular morphological deposits between the RPE and Bruch’s membrane. Both in vivo and in vitro experiments showed that RPE cells lacking SOCS2 displayed impaired autophagy, which could be recovered by re-expressing SOCS2. SOCS2 recognizes the ubiquitylated proteins and participates in the formation of autolysosome by binding with autophagy receptors and lysosome-associated membrane protein2 (LAMP-2), thereby regulating the phosphorylation of glycogen synthase kinase 3β (GSK3β) and mammalian target of rapamycin (mTOR) during the autophagy process. Our results imply that SOCS2 participates in ubiquitin-autophagy-lysosomal pathway and enhances autophagy by regulating GSK3β and mTOR. This study provides a potential therapeutic target for AMD.

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Lack of Socs2 expression reduces lifespan in high-growth mice

Cited by 11 publications

References 31 publications

Prevalent intron retention fine‐tunes gene expression and contributes to cellular senescence

Prevalent intron retention fine‐tunes gene expression and contributes to cellular senescence

Functional conservation in genes and pathways linking ageing and immunity

Suppressor of Cytokine Signaling 2 Regulates Retinal Pigment Epithelium Metabolism by Enhancing Autophagy

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