Identification of a set of KSRP target transcripts upregulated by PI3K-AKT signaling

Ruggiero, Tina; Trabucchi, Michèle; Ponassi, Marco; Corte, Giorgio; Chen, Ching-Yi; Al‐Haj, Latifa; Khabar, Khalid S.A.; Briata, Paola; Gherzi, Roberto

doi:10.1186/1471-2199-8-28

Cited by 58 publications

(51 citation statements)

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“…KSRP is a well-documented mRNA destabilizer that promotes decay of ARE-mRNAs through its association with the exosome, a large multiprotein complex (13,14). In this study, we show that the depletion of KSRP by siRNA transfection resulted in increases in both LDLR mRNA and protein levels.…”

Section: Identification Of Ldlr Mrna Binding Proteins 827mentioning

confidence: 50%

“…While hnRNP I is mostly known for its activity in regulation of RNA splicing (35), hnRNP D and KSRP have been shown to act as destabilizing trans-factors (14,16). To determine whether their destabilizing effects on LDLR mRNA are mediated through ARE sequences, we first conducted site-directed mutagenesis on the pLuc-UTR2 (19) construct to mutate the core ARE consensus sequence individually (Fig.…”

Section: Identification Of Hnrnp D I and Ksrp As Key Regulators Of mentioning

confidence: 99%

“…The destabilizing functions of ARE sequences are mediated through their interaction with ARE binding proteins (ARE-BPs) (12). Some ARE-BPs are decay promoting factors, such as KH-type splicing regulatory proteins (KSRPs), which interact with AREs and recruit RNA degradation machinery to the mRNA (13,14). Others are functional stabilizing trans-acting factors, such as embryonic lethal abnormal vision Drosophila-like 1 (ELAVL1), also known as HuR, that bind to ARE motifs and stabilize the ARE-mRNAs (12,15,16).…”

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confidence: 99%

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Identification of mRNA binding proteins that regulate the stability of LDL receptor mRNA through AU-rich elements

Chen

Zhou

et al. 2009

Journal of Lipid Research

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The 3′untranslated region (UTR) of human LDL receptor (LDLR) mRNA contains three AU-rich elements (AREs) responsible for rapid mRNA turnover and mediates the stabilization induced by berberine (BBR). However, the identities of the specific RNA binding proteins involved in the regulation of LDLR mRNA stability at the steady state level or upon BBR treatment are unknown. By conducting small interfering RNA library screenings, biotinylated RNA pull-down, mass spectrometry analysis, and functional assays, we now identify heterogeneous nuclear ribonucleoprotein D (hnRNP D), hnRNP I, and KH-type splicing regulatory protein (KSRP) as key modulators of LDLR mRNA stability in liver cells. We show that hnRNP D, I, and KSRP interact with AREs of the LDLR 3′UTR with sequence specificity. Silencing the expression of these proteins increased LDLR mRNA and protein levels. We further demonstrate that BBR-induced mRNA stabilization involves hnRNP I and KSRP, as their cellular depletions abolished the BBR effect and BBR treatment reduced the binding of hnRNP I and KSRP to the LDLR mRNA 3′UTR. These new findings demonstrate that LDLR mRNA stability is controlled by a group of ARE binding proteins, including hnRNP D, hnRNP I, and KSRP. Our results suggest that interference with the ability of destabilizing ARE binding proteins to interact with LDLR-ARE motifs is likely a mechanism for regulating LDLR expression by compounds such as BBR and perhaps

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Section: Identification Of Ldlr Mrna Binding Proteins 827mentioning

confidence: 50%

Section: Identification Of Hnrnp D I and Ksrp As Key Regulators Of mentioning

confidence: 99%

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confidence: 99%

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Identification of mRNA binding proteins that regulate the stability of LDL receptor mRNA through AU-rich elements

Chen

Zhou

et al. 2009

Journal of Lipid Research

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“…The expression of KHSRP, which is involved in the control of mRNA decay (Gherzi et al, 2006;Ruggiero et al, 2007) and plays a key role in the translation of DNA damage signalling to miRNA biogenesis (Trabucchi et al, 2009;Zhang et al, 2011) was increased in 3-month-old recuperated offspring. Although recuperated animals have reduced longevity (Jennings et al, 1999), which is associated with increased oxidative stress and an impaired response to DNA damage Tarry Adkins et al, 2009) the functional significance of the increase in KHSRP in the brain of these animals remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

5-HT2A and 5-HT2C receptors as hypothalamic targets of developmental programming in male rats

et al. 2016

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List of abbreviations5As the prevalence of obesity increases across the globe major efforts are directed at studying the mechanisms involved. Growing evidence suggests that susceptibility to obesity can be programmed by maternal and neonatal nutrition. In particular, individuals with low birth weight that undergo rapid postnatal growth are at higher risk of developing increased adiposity in later life. The molecular mechanisms mediating the interaction between early nutrition and obesity risk are, however, still largely unknown. Currently, there are no pharmacological therapies to prevent the increase in adiposity in individuals that underwent nutritional challenge in early life. Serotonin (5-HT) system is widely recognized as one of the key regulators of food intake and body weight. During fetal life serotonin also acts as a trophic factor that regulates brain development. As compounds targeting endogenous serotonin bioavailability have been among the most clinically effective treatments for obesity (e.g. d-fenfluramine), treatment targeting serotonin system may prevent the development of obesity in at risk individuals. Results:The study has shown that maternal protein restriction increased levels of serotonin in the blood of pregnant rat mums and in the placenta and the fetal brain. In adulthood the offspring had a reduced ability to sense serotonin, which was associated with a reduced hypothalamic expression of 5-HT2Creceptors -the primary serotonin receptor influencing appetite. As expected, reduced 5-HT2Creceptor expression was associated with impaired sensitivity to serotonin-mediated appetite suppression and hence could lead to increases in food intake. On the other hand offspring of low protein dams had a programmed increase in 5-HT2A receptors, which are positioned, just like 5-HT2C receptors, in the arcuate nucleus of the hypothalamus -a key area of the brain, involved in the control of food intake. Moreover, these animals were more sensitive to 5-HT2A receptor agonistinduced appetite suppression. Implications and future directions:This study identified a molecular mechanism that is involved in mediating the effects of suboptimal maternal diet on the regulation of food intake in the offspring. In addition, the authors showed that a treatment with 5-HT2A receptor agonist may potentially prevent the development of obesity in individuals that were exposed in utero to suboptimal nutrition and then underwent rapid postnatal growth. Non-hallucinogenic 5-HT2A receptor agonist should be used for such treatment. Combining the 5-HT2A receptor agonist with 5-HT2CR and 5-HT1BR agonists could potentially further increase the anorectic therapeutic effect. Disease Models & Mechanisms • DMM • Advance article AbstractThough obesity is a global epidemic, the physiological mechanisms involved are little understood.Recent advances reveal that susceptibility to obesity can be programmed by maternal and neonatal nutrition. Specifically, a maternal low protein diet during pregnancy causes decreased intrauterine growth, rapid...

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“…It was shown in HepG2 cells that HuR bound to the proximal ARE site of LDLR 3 ′ UTR and led to an increase in LDLR mRNA half-life. In addition to LDLR mRNA, these ARE-BPs have been shown to regulate the stability of other mRNA targets with diverse cellular functions including infl ammation, aging, and cell cycle (23)(24)(25)(26)(27). To date, there is no literature report describing the effect of sterols on the expression or activity of these LDLR mRNA binding proteins.…”

Section: Measurement Of Serum Lipid Levelsmentioning

confidence: 99%

A novel posttranscriptional mechanism for dietary cholesterol-mediated suppression of liver LDL receptor expression

Singh¹,

Kan²,

Shende³

et al. 2014

Journal of Lipid Research

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The expression of liver LDL receptor (LDLR) regulates human plasma LDL-cholesterol (LDL-C) homeostasis ( 1-3 ). Increased hepatic LDLR expression results in improved clearance of plasma LDL-C through receptor-mediated endocytosis, which is strongly associated with a decreased risk of developing cardiovascular disease in humans ( 4, 5 ). Thus far, many studies have demonstrated that intracellular cholesterol levels play a primary role in determination of hepatic LDLR expression levels through a negative feedback mechanism that controls gene transcription mediated by the sterolregulatory element (SRE) located in LDLR promoter and SRE binding proteins (SREBPs) ( 6, 7 ).In addition to transcriptional regulation, LDLR gene expression is subject to posttranscriptional regulation at the point of mRNA stability ( 8-11 ). It is well-known that mRNA stability plays a key role in the control of gene expression both by setting the basal level of gene expression and as a site of regulatory responses ( 12 ). In liver cells, when intracellular cholesterol levels rise, LDLR mRNA levels fall substantially along with transcripts of other SREBP target genes ( 13 ). While this decrease in LDLR mRNA abundance has been attributed to the transcriptional suppression due to the inhibition of proteolytic processing of SREBP ( 14, 15 ), it is currently unknown whether elevated cholesterol levels can also elicit a cellular response to increase LDLR mRNA turnover rate as a rapid means to

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Identification of a set of KSRP target transcripts upregulated by PI3K-AKT signaling

Cited by 58 publications

References 48 publications

Identification of mRNA binding proteins that regulate the stability of LDL receptor mRNA through AU-rich elements

Identification of mRNA binding proteins that regulate the stability of LDL receptor mRNA through AU-rich elements

5-HT2A and 5-HT2C receptors as hypothalamic targets of developmental programming in male rats

A novel posttranscriptional mechanism for dietary cholesterol-mediated suppression of liver LDL receptor expression

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