PI3K/AKT signaling determines a dynamic switch between distinct KSRP functions favoring skeletal myogenesis

Briata, Paola; Lin, Wei-Jye; Giovarelli, Matteo; Pasero, Michela; Chou, Chia-Fu; Trabucchi, Michèle; Mg, Rosenfeld; Chen, Ching-Yi; Gherzi, Roberto

doi:10.1038/cdd.2011.117

Cited by 71 publications

(86 citation statements)

References 41 publications

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“…KSRP participates in the control of gene expression in different ways, including the ARE-dependent rapid degradation of mRNAs and the maturation of miRNAs (5). By studying IL-6 mRNA, we obtained evidence that KSRP also limits translation of mRNAs through direct interaction with AREs.…”

Section: Discussionmentioning

confidence: 83%

Interleukin-1 Activates Synthesis of Interleukin-6 by Interfering with a KH-type Splicing Regulatory Protein (KSRP)-dependent Translational Silencing Mechanism

Dhamija

Kuehne

Winzen

et al. 2011

Journal of Biological Chemistry

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Inflammatory gene expression is controlled by post-transcriptional mechanisms. Many relevant transcripts contain AU-rich elements (AREs) 4 that can impose rapid degradation and restrict translation (1-3). Several proteins that interact with and mediate the effects of AREs have been identified. One of them, heterogeneous nuclear ribonucleoprotein K homology (KH)-type splicing regulatory protein (KSRP) is a member of the far upstream sequence element-binding proteins (4). It is a single-stranded nucleic acid-binding protein that contains four KH domains and has been reported to participate in transcription as well as splicing, editing, localization, and degradation of mRNAs and maturation of microRNA precursors (for a review, see Ref. 5). Most recently it has been found to contribute to regulation of RNA 3Ј-end processing (6).KSRP has been shown to facilitate mRNA degradation by directly binding to AREs and recruiting mRNA-degrading enzymes (7,8). Ksrp Ϫ/Ϫ cells and mice produce more type I interferons as a result of decreased mRNA decay and are refractory to viral infection (9). Different conditions of cellular activation or differentiation have been described to reduce KSRP binding and increase stability of specific mRNAs (e.g. Refs. 10 -13). The proinflammatory cytokine IL-1 can induce stabilization of KSRP target mRNAs, including that of IL-6 (14, 15), by reducing interaction of KSRP with the ARE presumably as a result of KSRP phosphorylation by p38 MAP kinase (10).IL-6, originally cloned as 26-kDa protein (16), IFN-␤2 (17), and BSF-2 (18), is a pleiotropic cytokine with important roles in inflammation, immune regulation, oncogenesis, and other physiological and pathological processes. Accordingly, interfering with IL-6 action is the aim of therapeutic strategies (19,20). IL-6 is induced in various cell types by a plethora of activators. Among the strongest and first identified are the proinflammatory cytokines tumor necrosis factor (TNF) (21) and IL-1 (22). Expression of IL-6 is controlled by transcriptional and post-transcriptional mechanisms. The latter involve AREs and a putative stem-loop structure that cause rapid degradation of the mRNA (23). Activators like IL-1 and lipopolysaccharide induce IL-6 mRNA stabilization through p38 MAPK/MK2 signaling (14, 24). IL-6 expression is also controlled by miRNAs (25,26).Our recent data showed that, in addition to stabilizing mRNAs, IL-1 can activate translation of mRNAs, including that of . We now provide evidence that repressed basal translation of IL-6 and a group of other mRNAs depends on KSRP. Interaction of KSRP with the IL-6 ARE is direct and is decreased in response to IL-1, suggesting a novel, miRNA-independent function for KSRP in translation.

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Section: Discussionmentioning

confidence: 83%

Interleukin-1 Activates Synthesis of Interleukin-6 by Interfering with a KH-type Splicing Regulatory Protein (KSRP)-dependent Translational Silencing Mechanism

Dhamija

Kuehne

Winzen

et al. 2011

Journal of Biological Chemistry

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“…Given that KSRP is a substrate of PI3K/AKT phosphorylation (29) and that stimulation of TLR4 by LPS activates the PI3K/AKT signaling pathway (30, 31), we hypothesized that PI3K/AKT signaling might be involved in sPIFinduced KSRP protein destabilization. Thus, we inhibited PI3K/ AKT signaling in RAW cells using an inhibitor specific for AKT (Akt Inh).…”

Section: Resultsmentioning

confidence: 99%

“…2 B and G). KSRP has important roles in both microRNA biogenesis and the regulation of mRNA stability (29). AKT-mediated KSRP phosphorylation at a unique serine residue (S193) through PI3K/AKT signaling induces KSRP association with protein 14-3-3 and impairs KSRP's ability to promote target mRNA degradation (50).…”

Section: Discussionmentioning

confidence: 99%

PreImplantation factor promotes neuroprotection by targeting microRNA let-7

Mueller

Zhou

Yang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

106

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Dysfunction and loss of neurons are the major characteristics of CNS disorders that include stroke, multiple sclerosis, and Alzheimer's disease. Activation of the Toll-like receptor 7 by extra-cellular micro-RNA let-7, a highly expressed microRNA in the CNS, induces neuronal cell death. Let-7 released from injured neurons and immune cells acts on neighboring cells, exacerbating CNS damage.Here we show that a synthetic peptide analogous to the mammalian PreImplantation factor (PIF) secreted by developing embryos and which is present in the maternal circulation during pregnancy inhibits the biogenesis of let-7 in both neuronal and immune cells of the mouse. The synthetic peptide, sPIF, destabilizes KH-type splicing regulatory protein (KSRP), a key microRNA-processing protein, in a Toll-like receptor 4 (TLR4)-dependent manner, leading to decreased production of let-7. Furthermore, s.c. administration of sPIF into neonatal rats following hypoxic-ischemic brain injury robustly rescued cortical volume and number of neurons and decreased the detrimental glial response, as is consistent with diminished levels of KSRP and let-7 in sPIF-treated brains. Our results reveal a previously unexpected mechanism of action of PIF and underscore the potential clinical utility of sPIF in treating hypoxic-ischemic brain damage. The newly identified PIF/TLR4/KSRP/ let-7 regulatory axis also may operate during embryo implantation and development.

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“…Ribonucleoprotein immunoprecipitation (RIP) assays were performed as described ( 45,46 ). Briefl y, cell lysates were immunoprecipitated with protein A/protein G beads coupled with anti-KSRP serum at 4°C overnight.…”

Section: Ribonucleoprotein Immunoprecipitation Assaysmentioning

confidence: 99%

KSRP is critical in governing hepatic lipid metabolism through controlling Per2 expression

Chou

Zhu

Lin

et al. 2015

Journal of Lipid Research

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PI3K/AKT signaling determines a dynamic switch between distinct KSRP functions favoring skeletal myogenesis

Cited by 71 publications

References 41 publications

Interleukin-1 Activates Synthesis of Interleukin-6 by Interfering with a KH-type Splicing Regulatory Protein (KSRP)-dependent Translational Silencing Mechanism

Interleukin-1 Activates Synthesis of Interleukin-6 by Interfering with a KH-type Splicing Regulatory Protein (KSRP)-dependent Translational Silencing Mechanism

PreImplantation factor promotes neuroprotection by targeting microRNA let-7

KSRP is critical in governing hepatic lipid metabolism through controlling Per2 expression

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