KSRP and MicroRNA 145 Are Negative Regulators of Lipolysis in White Adipose Tissue

Lin, Yi; Chou, Chu Fang; Giovarelli, Matteo; Briata, Paola; Gherzi, Roberto; Chen, Ching-Yi

doi:10.1128/mcb.00042-14

Cited by 51 publications

(50 citation statements)

References 31 publications

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“…miR-145. Recent evidence implicates miR-145 in adipocyte lipolysis (25,26). In mice, miR-145 is reported to suppress lipolysis in adipose tissue by inhibiting FOXO1 and CGI58 (25).…”

Section: Discussionmentioning

confidence: 99%

Integrative mRNA-microRNA analyses reveal novel interactions related to insulin sensitivity in human adipose tissue

Kirby

Walton

Finlin

et al. 2016

Physiological Genomics

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“…miR-145. Recent evidence implicates miR-145 in adipocyte lipolysis (25,26). In mice, miR-145 is reported to suppress lipolysis in adipose tissue by inhibiting FOXO1 and CGI58 (25).…”

Section: Discussionmentioning

confidence: 99%

Integrative mRNA-microRNA analyses reveal novel interactions related to insulin sensitivity in human adipose tissue

Kirby

Walton

Finlin

et al. 2016

Physiological Genomics

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“…The miR-135a has been found to target 3′UTR of foxo1 mRNA and inhibit its expression to promote BC cell proliferation (46). miR-145 acts as negative regulator of lipolysis in white adipose tissue through directly targeting and repressing FOXO1 (47). However, the regulation of miR-145 targeting FOXO1 seems inconsistent in cancer cells, because both of them are regarded as tumor suppressors.…”

Section: Disscussionmentioning

confidence: 99%

Role of STAT3 and FOXO1 in the Divergent Therapeutic Responses of Non-metastatic and Metastatic Bladder Cancer Cells to miR-145

Jiang

Huang

et al. 2017

Molecular Cancer Therapeutics

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Although miR-145 is the most frequently down-regulated miRNA in bladder cancer (BC), its exact stage-association and downstream effector have not been defined. Here, we found that miR-145 was upregulated in human BC patients with lymph node metastasis and in metastatic T24T cell line. Forced expression of miR-145 promoted anchorage-independent growth of T24T cells accompanied by the down-regulation of forkhead box class O1 (FOXO1). In contrast, in non-metastatic T24 cells, miR-145 overexpression inhibited cell growth with upregulation of FOXO1 and the knockdown of FOXO1 abolished the miR-145-mediated inhibition of cell growth. Mechanistic studies revealed that miR-145 directly bound to and attenuated 3′UTR activity of foxo1 mRNA in both T24 and T24T cells. Interestingly, miR-145 suppressed STAT3 phosphorylation at Tyr705 and increased foxo1 promoter transcriptional activity in T24 cells, but not in T24T cells, suggesting a role of STAT3 in the divergent responses to miR-145. Supporting this was our finding that STAT3 knockdown mimicked miR-145-mediated upregulation of FOXO1 in T24T cells and inhibition of anchorage-independent growth. Consistently, ectopic expression of miR-145 promoted tumor formation of xenograft T24T cells, whereas such promoting effect became inhibitory due to specific knockdown of STAT3. Together, our findings demonstrate the stage-specific association and function of miR-145 in BCs, and provide novel insights into the therapeutic targeting of miR-145.

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“…Briefly, KSRP recruits the RNA exosome and other enzymes to labile transcripts and promotes decay of inherently unstable mRNAs that encode factors critical for disparate cell functions (8,9). On the contrary, KSRP associates with Drosha and Dicer complexes and promotes maturation of precursors to generate miRNAs that exert important functions in cell proliferation, differentiation, and metabolism in response to extracellular stimuli (8,(10)(11)(12). The critical role exerted by KSRP in the myogenic differentiation of multipotent mesenchymal C2C12 cells and the profound transcriptome reshaping we recently described in these cells upon KSRP silencing (13,14) emphasizes the possibility that KSRP modulates a wide range of RNA targets.…”

mentioning

confidence: 99%

H19 long noncoding RNA controls the mRNA decay promoting function of KSRP

Giovarelli

Bucci

Ramos

et al. 2014

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

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109

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Long noncoding RNAs (lncRNAs) interact with protein factors to regulate different layers of gene expression transcriptionally or posttranscriptionally. Here we report on the functional consequences of the unanticipated interaction of the RNA binding protein K homology-type splicing regulatory protein (KSRP) with the H19 lncRNA (H19). KSRP directly binds to H19 in the cytoplasm of undifferentiated multipotent mesenchymal C2C12 cells, and this interaction favors KSRP-mediated destabilization of labile transcripts such as myogenin. AKT activation induces KSRP dismissal from H19 and, as a consequence, myogenin mRNA is stabilized while KSRP is repurposed to promote maturation of myogenic microRNAs, thus favoring myogenic differentiation. Our data indicate that H19 operates as a molecular scaffold that facilitates effective association of KSRP with myogenin and other labile transcripts, and we propose that H19 works with KSRP to optimize an AKT-regulated posttranscriptional switch that controls myogenic differentiation. Among small noncoding RNAs, microRNAs (miRNAs) repress gene expression by inhibiting translation and/or promoting decay of target mRNAs (1), with RBPs being able to control miRNA maturation from precursors or influence miRNA function (1, 2). A new class of transcripts referred to as long noncoding RNAs (lncRNAs, arbitrarily defined as longer than 200 nt) has recently moved to the forefront of regulatory RNA research (3). lncRNAs had been originally considered epigenetic regulators of gene expression, but the emphasis placed on the ways they regulate chromatin state likely obscures the full repertoire of their functions (4-6). Other roles of lncRNAs include posttranscriptional regulation, posttranslational control of protein activity, organization of protein complexes, as well as cell-cell signaling (4, 6). lncRNAs have been implicated in cellular events as different as cell cycle regulation, pluripotency, apoptosis, and DNA damage response, to name just a few (5, 6). Not surprisingly, lncRNA expression is altered in cancer, and it is becoming clear that some lncRNAs can control cell transformation by regulating vital cellular functions (7). Nevertheless, the composition and function of ribonucleoprotein complexes, including lncRNAs, is generally uncharacterized.Studies performed in primary and cultured cells as well as in mice proved that the K homology (KH)-type splicing regulatory protein (KSRP), a single-stranded RBP that interacts with nucleic acids through four hnRNP KH domains, is able to integrate different levels of gene expression and is required for proper immune response, lipid metabolism, cell fate decisions, and tissue regeneration (see ref. 8 for a recent review). We and others have found that KSRP negatively regulates gene expression via at least two distinct and integrated posttranscriptional mechanisms: (i) by promoting decay of unstable mRNAs [mainly targeting AU-rich elements (AREs) in their 3′UTRs] (8, 9) and (ii) by favoring maturation of select miRNAs from precursors (8, 10). Brie...

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KSRP and MicroRNA 145 Are Negative Regulators of Lipolysis in White Adipose Tissue

Cited by 51 publications

References 31 publications

Integrative mRNA-microRNA analyses reveal novel interactions related to insulin sensitivity in human adipose tissue

Integrative mRNA-microRNA analyses reveal novel interactions related to insulin sensitivity in human adipose tissue

Role of STAT3 and FOXO1 in the Divergent Therapeutic Responses of Non-metastatic and Metastatic Bladder Cancer Cells to miR-145

H19 long noncoding RNA controls the mRNA decay promoting function of KSRP

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