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miR-17 extends mouse lifespan by inhibiting senescence signaling mediated by MKP7
11] Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada [2] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
Abstract:
Here we show that transgenic expression of miR-17 extends lifespan and inhibits cellular senescence. We propose that miR-17 acts as a critical regulator of cellular senescence and tumorigenesis. We demonstrate that miR-17 targets both ADCY5 and IRS1, upregulating the downstream signals MKP7, FoxO3, LC3B, and HIF1α, and downregulating mTOR, c-myc, cyclin D1, and JNK. Silencing either ADCY5 or IRS1 promoted autophagy and repressed cellular senescence and apoptosis. Repression of ADCY5 by miR-17 translocated membrane-bound RGS2 into the nucleus, promoting interactions of RGS2 with HIF1α and the MKP7 promoter, enhancing MKP7 transcription. ADCY5 repression by miR-17 also facilitated the translocation of EGFR and MKP7 from membrane into cytoplasmic and mitochondrial fractions. Importantly, we found that MKP7 inhibited senescence by dephosphorylating PRAS40 at Thr246 and mTOR at Ser2248, facilitating the interaction and loss of function of both molecules. Thus, the oncogenic miR-17 also acts pleiotropically to inhibit cellular senescence and extend longevity.
Insights
Transgenic expression of microRNA-17 (miR-17) extends lifespan and inhibits cellular senescence by targeting ADCY5 and IRS1. This discovery reveals miR-17 as a key regulator of aging and cancer, offering new therapeutic avenues.
Area of Science:
- Molecular Biology
- Gerontology
- Oncology
Background:
- Cellular senescence is a key driver of aging and age-related diseases.
- MicroRNAs (miRNAs) are emerging as critical regulators of cellular processes, including senescence and tumorigenesis.
- The specific role of miR-17 in regulating lifespan and senescence remains incompletely understood.
Purpose of the Study:
- To investigate the role of miR-17 in regulating cellular senescence and lifespan.
- To identify the molecular targets and pathways modulated by miR-17 in the context of aging and cancer.
- To elucidate the mechanisms by which miR-17 influences senescence and longevity.
Main Methods:
- Transgenic expression of miR-17 in model organisms.
- Analysis of cellular senescence markers and apoptosis.
- Target validation using gene silencing and reporter assays.
- Western blotting and immunoprecipitation to assess protein interactions and modifications.
- Quantitative real-time PCR to measure gene expression levels.
Main Results:
- Transgenic miR-17 expression extended lifespan and inhibited cellular senescence.
- miR-17 directly targets ADCY5 and IRS1, modulating downstream signaling pathways.
- miR-17-mediated repression of ADCY5 and IRS1 promoted autophagy and repressed senescence and apoptosis.
- MKP7, a downstream target, inhibited senescence by dephosphorylating PRAS40 and mTOR.
- miR-17's actions on RGS2, HIF1α, EGFR, and MKP7 were elucidated, revealing complex regulatory networks.
Conclusions:
- miR-17 acts as a critical regulator of cellular senescence and tumorigenesis, extending lifespan.
- The study identifies ADCY5 and IRS1 as key targets of miR-17, mediating its anti-senescence effects.
- miR-17 pleiotropically inhibits cellular senescence and promotes longevity through multiple molecular mechanisms, including MKP7 activation.
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