The RNA-Binding Protein KSRP Promotes Decay of β-Catenin mRNA and Is Inactivated by PI3K-AKT Signaling

Gherzi, Roberto; Trabucchi, Michèle; Ponassi, Marco; Ruggiero, Tina; Corte, Giorgio; Moroni, Christoph; Chen, Ching-Yi; Khabar, Khalid S.A.; Andersen, Jens S.; Briata, Paola

doi:10.1371/journal.pbio.0050005

Cited by 139 publications

(199 citation statements)

References 54 publications

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“…Silencing experiments demonstrated that both Akt1 and Akt2 are required for DM-induced maturation of miR-1a, miR-133b and miR-206 (compare the expression of mature and primary miRNA in Figures 1c and d). In agreement with a role of AKT in myomiR maturation, expression of a membrane-bound myristoilated and constitutively active form of Akt2 (myr-AKT2 30 ) strongly enhanced the expression of myomiRs in C2C12 cells cultured in DM without affecting the expression of the corresponding pri-miRNAs (Figures 1e and f).…”

Section: Resultssupporting

confidence: 79%

“…26 KSRP distinct functions are regulated by different protein kinases, including MAPK p38, PI3K/AKT and ATM. 8,29,30 An unresolved issue is whether a specific signaling pathway regulates only a single KSRP function (i.e. affecting either mRNA decay or miRNA maturation) or is able to induce a dynamic change between KSRP functions in order to produce relevant phenotypes in a specific cellular context.…”

mentioning

confidence: 99%

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

Briata¹,

Lin

Giovarelli

et al. 2011

Cell Death Differ

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Skeletal myogenesis is orchestrated by distinct regulatory signaling pathways, including PI3K/AKT, that ultimately control muscle gene expression. Recently discovered myogenic micro-RNAs (miRNAs) are deeply implicated in muscle biology. Processing of miRNAs from their primary transcripts is emerging as a major step in the control of miRNA levels and might be well suited to be regulated by extracellular signals. Here we report that the RNA binding protein KSRP is required for the correct processing of primary myogenic miRNAs upon PI3K/AKT activation in myoblasts C2C12 and in the course of injury-induced muscle regeneration, as revealed by Ksrp knock-out mice analysis. PI3K/AKT activation regulates in opposite ways two distinct KSRP functions inhibiting its ability to promote decay of myogenin mRNA and activating its ability to favor maturation of myogenic miRNAs. This dynamic regulatory switch eventually contributes to the activation of the myogenic program.

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Section: Resultssupporting

confidence: 79%

mentioning

confidence: 99%

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

Briata¹,

Lin

Giovarelli

et al. 2011

Cell Death Differ

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“…However, it is possible that these additional activation events are consequent of the crosstalk between the Wnt pathway and MAPK or PI3K, described elsewhere [37,38]. Recently, Gherzi et al reported that the half-life of β-catenin mRNA is prolonged not only by Wnt but also by PI3K-Akt signalling, adding further complexity to the potential mechanisms by which insulin/IGF-1 could interact with Wnt signalling [39]. With the data available, we cannot dismiss the possibility that these different signalling events could converge to activate beta cell proliferation.…”

Section: Discussionmentioning

confidence: 98%

“…Little is known regarding the regulation of Sfrp5 expression. Of note, insulin, IGF-1 and other hormonal factors have been shown to activate the canonical Wnt signalling by increasing nuclear β-catenin content and binding of β-catenin/TCF to Wnt target gene promoters [39][40][41]. Thus, it is plausible that IGFBP3 and SFRP5 are two of the molecules mediating the crosstalk between the Wnt and insulin/IGF-1 signalling pathways at the level of pancreatic beta cells in the context of diet-induced obesity.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Sfrp5 promotes beta cell proliferation during obesity in the rat

et al. 2013

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Aims/hypothesis During obesity, the increment in beta cell mass in response to the rising demand for insulin is essential to maintain normal glucose homeostasis. However, the precise cellular and molecular mechanisms involved in beta cell mass plasticity remain poorly understood. The Wnt signalling pathway has been suggested as one possible modulator of beta cell proliferation, which represents the principal process involved in beta cell mass expansion. Here, we sought to determine the mechanisms involved in beta cell mass proliferation using diet-induced obese rats. Methods Wistar rats aged 8 weeks old were fed a standard or cafeteria diet. Global transcriptomic analysis of pancreatic rat islets was performed using microarray analysis. Genetic lossof-function approaches were performed in dispersed primary rat islets and the beta cell line INS1E. Gene expression was measured by real-time PCR, protein levels by immunoblot analysis, proliferation rates by ELISA and apoptosis by flow cytometry. Results Sfrp5, coding for secreted frizzled-related protein 5, is downregulated in the pancreatic islets of cafeteria-diet-fed rats as well as in the pancreatic islets of human obese patients. We demonstrate that silencing Sfrp5 increases beta cell proliferation, which correlates with activation of Wnt signalling and enhanced levels of proliferation markers. In addition, we show that expression of Sfrp5 in beta cells is modulated by IGF binding protein 3 (IGFBP3) secreted from visceral adipose tissue. Conclusions/interpretation Together, these findings reveal an important role for SFRP5 and Wnt signalling in the regulation of beta cell proliferation in obesity.

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“…In addition to the components of translational machinery, RNA-binding proteins are also aberrantly expressed in tumors, including PTB (He et al, 2007), HuR (Lopez de Silanes et al, 2003), KH domain-containing protein, and hnRNPD among others (Gouble et al, 2002), with a direct correlation between abnormal expression of a particular RNA-binding protein and tumor formation (CRD-BP) in breast tissue (Tessier et al, 2004). Furthermore, many RNA-binding proteins have been reported to be direct targets of Akt, including YB-1 (Evdokimova et al, 2006), the tumor suppressor Pdcd4 (Palamarchuk et al, 2005), BRF1 (Benjamin et al, 2006) and KSRP (Gherzi et al, 2006), thus linking the Akt pathway to mRNA silencing, degradation, apoptosis and the Wnt signaling pathway through the promotion of the stabilization of b-catenin mRNA, respectively.…”

Section: Introductionmentioning

confidence: 99%

Akt phosphorylation of La regulates specific mRNA translation in glial progenitors

et al. 2008

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The Akt signaling pathway activity increases as normal tissue progresses to malignant transformation, and regulates the translation of specific messenger RNAs (mRNAs) through multiple mechanisms. We have identified one such mechanism of Akt-dependent translation control as involving the lupus autoantigen La. La is an RNA-associated protein that contains multiple trafficking elements to support the interaction with RNAs in different subcellular locations. We show here that the La protein is a direct target of the serine/threonine protein kinase Akt on threonine 301, and La nuclear export in mouse glial progenitors, as well as its association with polysomes is modulated by Akt activity. Using a functional approach to determine the network of genes affected by La in the cytoplasm by microarray analysis of polysome-bound mRNAs, we found that La binds 34% of the polysome bound mRNAs and regulates the expression of a specific pool of mRNAs under KRas/Akt activation. Therefore, La appears to be an important contributor to Aktmediated translational regulation of these transcripts in murine glial cells.

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The RNA-Binding Protein KSRP Promotes Decay of β-Catenin mRNA and Is Inactivated by PI3K-AKT Signaling

Cited by 139 publications

References 54 publications

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

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

Downregulation of Sfrp5 promotes beta cell proliferation during obesity in the rat

Akt phosphorylation of La regulates specific mRNA translation in glial progenitors

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