Rapamycin induces pluripotent genes associated with avoidance of replicative senescence

Поспелова, Т. В.; Быкова, Т. В.; Зубова, С. Г.; Katolikova, N.; Yartzeva, Natalia M; Поспелов, В. А.

doi:10.4161/cc.27396

Cited by 25 publications

(20 citation statements)

References 141 publications

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“…Our study is consistent with previous findings. As a key drug in our experiments, rapamycin is a highly specific inhibitor of mTORC1 and has been used as a clinical immunosuppressant in organ transplantation and as an antiangiogenic agent in clinical trials for treatment of cancers and other vascular diseases [44, 45]. Interestingly, rapamycin has been reported to inhibit tumor angiogenesis through impairment of HIF-1α/VEGF production in some human cancer cell lines [46], which is consistent with our experimental results.…”

Section: Discussionsupporting

confidence: 80%

DEPTOR Deficiency-Mediated mTORc1 Hyperactivation in Vascular Endothelial Cells Promotes Angiogenesis

Ding

Shan

Nai

et al. 2018

Cell Physiol Biochem

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Background/Aims: The mechanistic target of rapamycin (mTOR) signaling pathway is essential for angiogenesis and embryonic development. DEP domain-containing mTOR-interacting protein (DEPTOR) is an mTOR binding protein that functions to inhibit the mTOR pathway In vitro experiments suggest that DEPTOR is crucial for vascular endothelial cell (EC) activation and angiogenic responses. However, knowledge of the effects of DEPTOR on angiogenesis in vivo is limited. This study aimed to determine the role of DEPTOR in tissue angiogenesis and to elucidate the molecular mechanisms. Methods: Cre/loxP conditional gene knockout strategy was used to delete the Deptor gene in mouse vascular ECs. The expression or distribution of cluster of differentiation 31 (CD31), vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1 alpha (HIF-1α) were detected by immunohistochemical staining or western blot. Tube formation assay was used to measure angiogenesis in vitro. Results: Deptor knockdown led to increased expression of CD31, VEGF and HIF-1α in heart, liver, kidney and aorta. After treatment with rapamycin, their expression was significantly down regulated. In vitro, human umbilical vein endothelial cells (HUVECs) were transfected with DEPTOR-specific small interfering RNA (siRNA), which resulted in a significant increase in endothelial tube formation and migration rates. In contrast, DEPTOR overexpression markedly reduced the expression of CD31, VEGF and HIF-1α. Conclusions: Our findings demonstrated that deletion of the Deptor gene in vascular ECs resulted in upregulated expression of CD31 and HIF-1α, and further stimulated the expression of VEGF which promoted angiogenesis, indicating that disruption of normal angiogenic pathways may occur through hyperactivation of the mTORC1/HIF-1α/VEGF signaling pathway.

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Section: Discussionsupporting

confidence: 80%

DEPTOR Deficiency-Mediated mTORc1 Hyperactivation in Vascular Endothelial Cells Promotes Angiogenesis

Ding

Shan

Nai

et al. 2018

Cell Physiol Biochem

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“…oct-4, sox-2 and nanog, which is unrelated to autophagy. 34 The lack of specificity of rapamycin and other chemical agents, such as chloroquine, has been acknowledged and might be the most important weakness in many autophagy reports. 35,36 Chloroquine is an anti-malaria drug, which blocks lysosome function and has therefore a major impact on cell growth and survival.…”

Section: Discussionmentioning

confidence: 99%

The impact of autophagy on the development of senescence in primary tubular epithelial cells

et al. 2016

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Autophagy and senescence are 2 distinct pathways that are importantly involved in acute kidney injury and renal repair. Recent data indicate that the 2 processes might be interrelated. To investigate the potential link between autophagy and senescence in the kidney we isolated primary tubular epithelial cells (PTEC) from wild-type mice and monitored the occurrence of cellular senescence during autophagy activation and inhibition. We found that the process of cell isolation and transfer into culture was associated with a strong basal autophagic activation in PTEC. Specific inhibition of autophagy by silencing autophagy-related 5 (Atg5) counteracted the occurrence of senescence hallmarks under baseline conditions. Reduced senescent features were also observed in Atg5 silenced PTEC after g-irradiation and during H-Ras induced oncogenic senescence, but the response was less uniform in these stress models. Senescence inhibition was paralleled by better preservation of a mature epithelial phenotype in PTEC. Interestingly, treatment with rapamycin, which acts as an activator of autophagy, also counteracted the occurrence of senescence features in PTEC. While we interpret the anti-senescent effect of rapamycin as an autophagy-independent effect of mTOR-inhibition, the more specific approach of Atg5 silencing indicates that overactivated autophagy can have pro-senescent effects in PTEC. These results highlight the complex interaction between cell culture dependent stress mechanisms, autophagy and senescence.

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“…The mammalian target of rapamycin (mTOR) pathway may represent another important biological mechanism linking telomeric aging to obesity, because mTOR pathway integrates insulin and nutrient signaling in numerous cell types and enhanced mTOR signaling has been implicated in cellular senescence. [31-33] Moreover, hyperactivity of the mTOR signaling has been associated with obesity and its related traits such as insulin resistance, type 2 diabetes, and cardiovascular diseas [34-37]. Furthermore, rapamycin slows down aging, prevents age-related diseases and extends maximal lifespan in mice [37].…”

Section: Discussionmentioning

confidence: 99%

Short leukocyte telomere length is associated with obesity in American Indians: The strong heart family study

Chen

Yeh

Lin

et al. 2014

Aging

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Shorter leukocyte telomere length (LTL) has been associated with a wide range of age-related disorders including cardiovascular disease (CVD) and diabetes. Obesity is an important risk factor for CVD and diabetes. The association of LTL with obesity is not well understood. This study for the first time examines the association of LTL with obesity indices including body mass index, waist circumference, percent body fat, waist-to-hip ratio, and waist-to-height ratio in 3,256 American Indians (14-93 years old, 60% women) participating in the Strong Heart Family Study. Association of LTL with each adiposity index was examined using multivariate generalized linear mixed model, adjusting for chronological age, sex, study center, education, lifestyle (smoking, alcohol consumption, and total energy intake), high-sensitivity C-reactive protein, hypertension and diabetes. Results show that obese participants had significantly shorter LTL than non-obese individuals (age-adjusted P=0.0002). Multivariate analyses demonstrate that LTL was significantly and inversely associated with all of the studied obesity parameters. Our results may shed light on the potential role of biological aging in pathogenesis of obesity and its comorbidities.

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Rapamycin induces pluripotent genes associated with avoidance of replicative senescence

Cited by 25 publications

References 141 publications

DEPTOR Deficiency-Mediated mTORc1 Hyperactivation in Vascular Endothelial Cells Promotes Angiogenesis

DEPTOR Deficiency-Mediated mTORc1 Hyperactivation in Vascular Endothelial Cells Promotes Angiogenesis

The impact of autophagy on the development of senescence in primary tubular epithelial cells

Short leukocyte telomere length is associated with obesity in American Indians: The strong heart family study

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