miR-17 extends mouse lifespan by inhibiting senescence signaling mediated by MKP7

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.

MicroRNA‐17 regulates autophagy to promote hepatic ischemia/reperfusion injury via suppression of signal transductions and activation of transcription‐3 expression

“…Moreover, the autophagic activation by anti‐miR‐17 decreases the threshold of temozolomide resistance in T98G cells . MiR‐17 also targets both ADCY5 and insulin receptor substrate 1 to promote autophagy and repress cellular senescence and apoptosis …”

MicroRNA-17-5p: At the Crossroads of Cancer and Aging - A Mini-Review

“…As shown in figure 3b, inhibition of mTOR by miR-17-5p upregulates autophagy and slows down the aging process in the mouse model presented by Du et al [28], discussed in the section A Long-Lived Pre-miR-17 Overexpressing Mouse Model. Indeed, oncogenic miRNAs like miR-17 are upregulated in rapamycin-resistant cells and inhibition of miR-17 restored rapamycin sensitivity.…”

“…The interest in the role of miR-17-5p in aging research has peaked with the report that its overexpression in mouse extends the organismal lifespan by approximately 16% [28]. This finding was somewhat surprising after the same authors had previously observed that miR-17 represses fibronectin expression, leading to cellular defects, growth retardation, smaller organs and strongly reduced hematopoietic cell lineages in miR-17-overexpressing mice [29], results that do not seem well reconciled yet.…”

“…In addition, MKP7 acts as a negative regulator of c-Jun amino-terminal kinase and extracellular signal-regulated kinase (ERK) pathways. ERKs function in the control of cell division, and inhibitors of these enzymes are potential anticancer agents, hence miR-17-5p might also extend the organismal life span by reducing cancer risk, but that is still subject to speculation, since - as stated above - miR-17 transgenic mice develop liver tumors [28]. The authors do not give any information about the causes of death in their miR-17 mice, and a potential confounder might be that both miR-17-5p and miR-17-3p are expressed from the pre-miR-17 construct to a comparable degree, and hence the relative effect of each specific miRNA to the observed organismal phenotype cannot be determined [28].…”

Anti-tumor activity of miR-17 in melanoma

“…Accumulating evidence shows that abnormal expression of miRNAs in tumors can lead to changes in the intrinsic properties of cancer cells, which include cell proliferation, migration, apoptosis, and cellular senescence. 1 Recent research from our lab has implicated the importance of miR-17 expression in the adaptability of tumor cells to environmental fluctuations using the glioblastoma cell line. These cells, which are highly adaptive and over-express miR-17, appeared to adopt a new strategy to cope with the lack of nutrition in the environment by lowering their metabolic rate.…”