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Kotb Abdelmohsen,
Amaresh Panda,
Min-Ju Kang,
Jason Xu,
Roza Selimyan,
Je-Hyun Yoon,
Jennifer L Martindale,
Supriyo De,
William H Wood,
Kevin G Becker, Myriam Gorospe
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ABSTRACT: Non-coding RNAs include small transcripts, such as microRNAs and piwi-interacting RNAs, and a wide range of long non-coding RNAs (lncRNAs). Although many lncRNAs have been identified, only a small number of lncRNAs have been characterized functionally. Here, we sought to identify lncRNAs differentially expressed during replicative senescence. We compared lncRNAs expressed in proliferating, early passage, 'young' human diploid WI-38 fibroblasts [population doubling (PDL) 20] with those expressed in senescent, late-passage, 'old' fibroblasts (PDL 52) by RNA sequencing (RNA-Seq). Numerous transcripts in all lncRNA groups (antisense lncRNAs, pseudogene-encoded lncRNAs, previously described lncRNAs and novel lncRNAs) were validated using reverse transcription (RT) and real-time, quantitative (q)PCR. Among the novel senescence-associated lncRNAs (SAL-RNAs) showing lower abundance in senescent cells, SAL-RNA1 (XLOC_023166) was found to delay senescence, since reducing SAL-RNA1 levels enhanced the appearance of phenotypic traits of senescence, including an enlarged morphology, positive β-galactosidase activity, and heightened p53 levels. Our results reveal that the expression of known and novel lncRNAs changes with senescence and suggest that SAL-RNAs play direct regulatory roles in this important cellular process. This article is protected by copyright. All rights reserved.
Aging cell 06/2013; · 7.55 Impact Factor
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Emmette R Hutchison,
Elisa M Kawamoto,
Dennis D Taub,
Ashish Lal,
Kotb Abdelmohsen,
Yongqing Zhang,
William H Wood,
Elin Lehrmann,
Simonetta Camandola,
Kevin G Becker, Myriam Gorospe,
Mark P Mattson
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ABSTRACT: Inflammation is a common component of acute injuries of the central nervous system (CNS) such as ischemia, and degenerative disorders such as Alzheimer's disease. Glial cells play important roles in local CNS inflammation, and an understanding of the roles for microRNAs in glial reactivity in injury and disease settings may therefore lead to the development of novel therapeutic interventions. Here, we show that the miR-181 family is developmentally regulated and present in high amounts in astrocytes compared to neurons. Overexpression of miR-181c in cultured astrocytes results in increased cell death when exposed to lipopolysaccharide (LPS). We show that miR-181 expression is altered by exposure to LPS, a model of inflammation, in both wild-type and transgenic mice lacking both receptors for the inflammatory cytokine TNF-α. Knockdown of miR-181 enhanced LPS-induced production of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, IL-8) and HMGB1, while overexpression of miR-181 resulted in a significant increase in the expression of the anti-inflammatory cytokine IL-10. To assess the effects of miR-181 on the astrocyte transcriptome, we performed gene array and pathway analysis on astrocytes with reduced levels of miR-181b/c. To examine the pool of potential miR-181 targets, we employed a biotin pull-down of miR-181c and gene array analysis. We validated the mRNAs encoding MeCP2 and X-linked inhibitor of apoptosis as targets of miR-181. These findings suggest that miR-181 plays important roles in the molecular responses of astrocytes in inflammatory settings. Further understanding of the role of miR-181 in inflammatory events and CNS injury could lead to novel approaches for the treatment of CNS disorders with an inflammatory component.
Glia 05/2013; · 4.82 Impact Factor
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ABSTRACT: The RNA-binding protein TIAR is an mRNA-binding protein that acts as a translational repressor, particularly important under conditions of cellular stress. It binds to target mRNA and DNA via its RNA recognition motif (RRM) domains and is involved in both splicing regulation and translational repression via the formation of "stress granules." TIAR has also been shown to bind ssDNA and play a role in the regulation of transcription. Here we show, using surface plasmon resonance and nuclear magnetic resonance spectroscopy, specific roles of individual TIAR domains for high-affinity binding to RNA and DNA targets. We confirm that RRM2 of TIAR is the major RNA- and DNA-binding domain. However, the strong nanomolar affinity binding to U-rich RNA and T-rich DNA depends on the presence of the six amino acid residues found in the linker region C-terminal to RRM2. On its own, RRM1 shows preferred binding to DNA over RNA. We further characterize the interaction between RRM2 with the C-terminal extension and an AU-rich target RNA sequence using NMR spectroscopy to identify the amino acid residues involved in binding. We demonstrate that TIAR RRM2, together with its C-terminal extension, is the major contributor for the high-affinity (nM) interactions of TIAR with target RNA sequences.
RNA biology 04/2013; 10(4). · 5.56 Impact Factor
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ABSTRACT: MicroRNAs (miRNAs) are potent post-transcriptional regulators of gene expression. In mammalian cells, miRNAs typically suppress mRNA stability and/or translation through partial complementarity with target mRNAs. Each miRNA can regulate a wide range of mRNAs, and a single mRNA can be regulated by multiple miRNAs. Through these complex regulatory interactions, miRNAs participate in many cellular processes, including carcinogenesis. By altering gene expression patterns, cancer cells can develop specific phenotypes that allow them to proliferate, survive, secure oxygen and nutrients, evade immune recognition, invade other tissues and metastasize. At the same time, cancer cells acquire miRNA signature patterns distinct from those of normal cells; the differentially expressed miRNAs contribute to enabling the cancer traits. Over the past decade, several miRNAs have been identified, which functioned as oncogenic miRNAs (oncomiRs) or tumor-suppressive miRNAs (TS-miRNAs). In this review, we focus specifically on TS-miRNAs and their effects on well-established cancer traits. We also discuss the rising interest in TS-miRNAs in cancer therapy.
International Journal of Molecular Sciences 01/2013; 14(1):1822-42. · 2.60 Impact Factor
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ABSTRACT: Eukaryotic cells transcribe a vast number of noncoding RNA species. Among them, long noncoding RNAs (lncRNAs) have been widely implicated in the regulation of gene transcription. However, examples of post-transcriptional gene regulation by lncRNAs are emerging. For example, through extended base-pairing, lncRNAs can stabilize or promote the translation of target mRNAs, while partial base-pairing facilitates mRNA decay or inhibits target mRNA translation. In the absence of complementarity, lncRNAs can suppress pre-mRNA splicing and translation by acting as decoys of RNA-binding proteins or microRNAs, and can compete for microRNA-mediated inhibition leading to increased expression of the mRNA. Through these regulatory mechanisms, lncRNAs can elicit differentiation, proliferation, and cytoprotective programs, underscoring the rising recognition of lncRNA roles in human disease. In this review, we summarize the mechanism of post-transcriptional gene regulation by lncRNAs.
Journal of Molecular Biology 11/2012; · 4.00 Impact Factor
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ABSTRACT: RNA-binding proteins CUG-binding protein 1 (CUGBP1) and HuR are highly expressed in epithelial tissues and modulate the stability and translation of target mRNAs. Here, we present evidence that CUGBP1 and HuR jointly regulate the translation of occludin and play a crucial role in the maintenance of tight junction (TJ) integrity in the intestinal epithelial cell monolayer. CUGBP1 and HuR competed for association with the same occludin 3'-untranslated region element and regulated occludin translation competitively and in opposite directions. CUGBP1 overexpression decreased HuR binding to occludin mRNA, repressed occludin translation, and compromised the TJ barrier function, whereas HuR overexpression inhibited CUGBP1 association with occludin mRNA and promoted occludin translation, thereby enhancing the barrier integrity. Repression of occludin translation by CUGBP1 was due to the colocalization of CUGBP1 and tagged occludin RNA in processing bodies (P-bodies), and this colocalization was prevented by HuR overexpression. These findings indicate that CUGBP1 represses occludin translation by increasing occludin mRNA recruitment to P-bodies, whereas HuR promotes occludin translation by blocking occludin mRNA translocation to P-bodies via the displacement of CUGBP1.
Molecular biology of the cell 11/2012; · 5.98 Impact Factor
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ABSTRACT: A hallmark trait of cellular senescence is the acquisition of a senescence-associated secretory phenotype (SASP). SASP factors include cytokines and their receptors (IL-6, IL-8, osteoprotegerin, GM-CSF), chemokines and their ligands (MCP-1, HCC4), and oncogenes (Gro1 and Gro2), many of them encoded by mRNAs whose stability and translation are tightly regulated. Using two models of human fibroblast senescence (WI-38 and IDH4 cells), we report the identification of RNA-binding protein NF90 as a post-transcriptional repressor of several SASP factors. In 'young', proliferating fibroblasts, NF90 was highly abundant, associated with numerous SASP mRNAs, and inhibited their expression. By contrast, senescent cells expressed low levels of NF90, thus allowing SASP factor expression to increase. NF90 elicited these effects mainly by repressing the translation of target SASP mRNAs, since silencing NF90 did not increase the steady-state levels of SASP mRNAs but elevated key SASP factors including MCP-1, GROa, IL-6, and IL-8. Our findings indicate that NF90 contributes to maintaining low levels of SASP factors in non-senescent cells, while NF90 reduction in senescent cells allows SASP factor expression to rise.
Aging 10/2012; · 5.13 Impact Factor
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ABSTRACT: MicroRNA (miRNA) biogenesis is tightly regulated by numerous proteins. Among them, Dicer is required for the processing of the precursor (pre-)miRNAs into the mature miRNA. Despite its critical function, the mechanisms that regulate Dicer expression are not well understood. Here we report that the RNA-binding protein (RBP) AUF1 (AU-binding factor 1) associates with the endogenous DICER1 mRNA and can interact with several segments of DICER1 mRNA within the coding region (CR) and the 3'-untranslated region (UTR). Through these interactions, AUF1 lowered DICER1 mRNA stability, since silencing AUF1 lengthened DICER1 mRNA half-life and increased Dicer expression, while overexpressing AUF1 lowered DICER1 mRNA and Dicer protein levels. Given that Dicer is necessary for the synthesis of mature miRNAs, Given that Dicer is necessary for the synthesis of mature miRNAs, the lowering of Dicer levels by AUF1 diminished the levels of miRNAs tested, but not the levels of the corresponding pre-miRNAs. In summary, AUF1 suppresses miRNA production by reducing Dicer production.
Nucleic Acids Research 10/2012; · 8.03 Impact Factor
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ABSTRACT: Primary lung tumors, breast tumors, and melanoma metastasize mainly in the brain where therapy is limited to surgery and radiation. To investigate the molecular basis of brain metastases, we isolated brain-trophic metastatic MDA-MB-435-LvBr2 (LvBr2) cells via left ventricle (LV) injection of MDA-MB-435 cells into immunodeficiency (NOD/SCID) mice. Whereas parent MDA-MB-435 cells displayed an elongated morphology, LvBr2 cells were round and displayed an aggregated distribution. LvBr2 cells expressed lower β-catenin levels and higher heterogeneous nuclear ribonucleoprotein C1/C2 (hnRNPC) levels than parental cells. Since microRNAs are known to play an important role in cancer progression including metastasis, we screened microRNAs expressed specifically in brain metastases. MicroRNA-146a was almost undetectable in LvBr2 cells and highly expressed in the parental cells. Overexpression of miR-146a increased β-catenin expression and suppressed the migratory and invasive activity of LvBr2 cells. The miR-146a-elicited decrease in hnRNPC in turn lowered the expression of MMP-1, uPA, and uPAR and inhibited the migratory and invasive activity of LvBr2 cells. Taken together, our findings indicate that miR-146a is virtually absent from brain metastases and can suppress their metastatic potential including their migratory and invasive activities associated with upregulation of β-catenin and downregulation of hnRNPC.
Molecules and Cells 09/2012; 34(3):329-34. · 2.18 Impact Factor
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ABSTRACT: MicroRNAs (miRNAs) have been implicated in the pathogenesis and progression of brain tumors. miR-21 is one of the most highly overexpressed miRNAs in glioblastoma multiforme (GBM), and its level of expression correlates with the tumor grade. Programmed cell death 4 (PDCD4) is a well-known miR-21 target and is frequently downregulated in glioblastomas in accordance with increased miR-21 expression. Downregulation of miR-21 or overexpression of PDCD4 can inhibit metastasis. Here, we investigate the role of heterogeneous nuclear ribonucleoprotein C1/C2 (hnRNPC) in the metastatic potential of the glioblastoma cell line T98G. hnRNPC bound directly to primary miR-21 (pri-miR-21) and promoted miR-21 expression in T98G cells. Silencing of hnRNPC lowered miR-21 levels, in turn increasing the expression of PDCD4, suppressing Akt and p70S6K activation, and inhibiting migratory and invasive activities. Silencing of hnRNPC reduced cell proliferation and enhanced etoposide-induced apoptosis. In support of a role for hnRNPC in the invasiveness of GBM, highly aggressive U87MG cells showed higher hnRNPC expression levels and hnRNPC abundance in tissue arrays and also showed elevated levels as a function of brain tumor grade. Taken together, our data indicate that hnRNPC controls the aggressiveness of GBM cells through the regulation of PDCD4, underscoring the potential usefulness of hnRNPC as a prognostic and therapeutic marker of GBM.
Molecular and cellular biology 08/2012; 32(20):4237-44. · 6.06 Impact Factor
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Danielle M Pineda,
David W Rittenhouse,
Christopher C Valley,
Joseph A Cozzitorto,
Richard A Burkhart,
Benjamin Leiby,
Jordan M Winter,
Matthew C Weber,
Eric R Londin,
Isidore Rigoutsos,
Charles J Yeo, Myriam Gorospe,
Agnieska K Witkiewicz,
Jonathan N Sachs,
Jonathan R Brody
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ABSTRACT: Apoptosis is one of the core signaling pathways disrupted in pancreatic ductal adenocarcinoma (PDA). Death receptor 5 (DR5) is a member of the tumor necrosis factor (TNF)-receptor superfamily that is expressed in cancer cells. Binding of TNF-related apoptosis-inducing ligand (TRAIL) to DR5 is a potent trigger of the extrinsic apoptotic pathway, and numerous clinical trials are based on DR5-targeted therapies for cancer, including PDA. Human antigen R (HuR), an RNA-binding protein, regulates a select number of transcripts under stress conditions. Here we report that HuR translocates from the nucleus to the cytoplasm of PDA cells upon treatment with a DR5 agonist. High doses of DR5 agonist induce cleavage of both HuR and caspase 8. HuR binds to DR5 mRNA at the 5'-untranslated region (UTR) in PDA cells in response to different cancer-associated stressors and subsequently represses DR5 protein expression; silencing HuR augments DR5 protein production by enabling its translation and thus enhances apoptosis. In PDA specimens (n = 53), negative HuR cytoplasmic expression correlated with elevated DR5 expression (odds ratio 16.1, p < 0.0001). Together, these data demonstrate a feedback mechanism elicited by HuR-mediated repression of the key apoptotic membrane protein DR5.
Cancer biology & therapy 08/2012; 13(10):946-55. · 2.64 Impact Factor
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ABSTRACT: Mammalian long intergenic noncoding RNAs (lincRNAs) are best known for modulating transcription. Here we report a posttranscriptional function for lincRNA-p21 as a modulator of translation. Association of the RNA-binding protein HuR with lincRNA-p21 favored the recruitment of let-7/Ago2 to lincRNA-p21, leading to lower lincRNA-p21 stability. Under reduced HuR levels, lincRNA-p21 accumulated in human cervical carcinoma HeLa cells, increasing its association with JUNB and CTNNB1 mRNAs and selectively lowering their translation. With elevated HuR, lincRNA-p21 levels declined, which in turn derepressed JunB and β-catenin translation and increased the levels of these proteins. We propose that HuR controls translation of a subset of target mRNAs by influencing lincRNA-p21 levels. Our findings uncover a role for lincRNA as a posttranscriptional inhibitor of translation.
Molecular cell 07/2012; 47(4):648-55. · 14.61 Impact Factor
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ABSTRACT: Cellular transcripts of all types, including coding messenger (m)RNAs and noncoding (nc)RNAs, are subject to extensive post-transcriptional regulation. Among the factors that elicit post-transcriptional control, microRNAs (miRNAs) have emerged as a major class of small regulatory RNAs. Since RNA-RNA interactions can be modeled computationally, several excellent programs have been developed to predict the interaction of miRNAs with target transcripts. However, many such predictions are not realized for different reasons, including absent or low-abundance expression of the miRNA in the cell, the existence of competing factors or conformational changes masking the microRNA site, and the possibility that target transcripts are not present in the prediction databases, as is the case for long ncRNAs. Here, we provide a systematic approach termed MS2-TRAP (tagged RNA affinity purification) for identifying miRNAs associated with a target transcript in the cellular context. We illustrate the use of this methodology by identifying microRNAs that associate with a long intergenic (li)ncRNA, based on the expression of the lincRNA tagged with MS2 RNA hairpins (lincRNA-p21-MS2) and the concomitant expression of a fusion protein recognizing the MS2 RNA hairpins, MS2-GST. After affinity pulldown of the ribonucleoprotein (RNP) complex comprising [MS2-GST/lincRNA-p21-MS2], the RNA in the pulldown material was isolated and reverse transcribed (RT). Subsequent assessment of the microRNAs present in the pulldown complex by using real-time quantitative (q)PCR analysis led to the identification of bona fide miRNAs that interact with and control the abundance of lincRNA-p21. We describe alternative designs and applications of this approach, and discuss its implications in deciphering post-transcriptional gene regulatory schemes.
Methods 07/2012; · 4.01 Impact Factor
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ABSTRACT: The mammalian RNA-binding protein (RBP) HuR associates with numerous mRNAs encoding proteins with roles in cell division, cell survival, immune response, and differentiation. HuR was known to stabilize many of these mRNAs and/or modulated their translation, but the molecular processes by which HuR affected the fate of target mRNAs was largely unknown. Evidence accumulated over the past five years has revealed that the influence of HuR on many bound transcripts depends on HuR's interplay with microRNAs which associate with the same mRNAs. Here, we review the interactions of HuR and microRNAs - both competitive and cooperative - that govern expression of shared target mRNAs. Competition between HuR and microRNAs typically results in enhanced gene expression if the HuR-mRNA interaction prevails, and in repression if the microRNA remains associated. Cooperation between HuR and microRNAs leads to lower expression of the shared mRNA. We also describe the regulation of HuR levels by microRNAs as well as the regulation of microRNA levels by HuR. Finally, we discuss transcriptome-wide analyses of HuR-bound mRNAs with neighboring microRNA sites, and review the emerging mechanisms whereby microRNAs confer versatility and robustness to the post-transcriptional outcomes of HuR targets.
Current Protein and Peptide Science 06/2012; 13(4):372-9. · 2.89 Impact Factor
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ABSTRACT: Nucleolin is a multifunctional protein localized primarily in the nucleolus, but also found in the nucleoplasm, cytoplasm and cell membrane. It is involved in several aspects of DNA metabolism, and participates extensively in RNA regulatory mechanisms, including transcription, ribosome assembly, mRNA stability and translation, and microRNA processing. Nucleolin's implication in disease is linked to its ability to associate with target RNAs via its four RNA-binding domains and its arginine/glycin-rich domain. By modulating the post-transcriptional fate of target mRNAs, which typically bear AU-rich and/or G-rich elements, nucleolin has been linked to cellular events that influence disease, notably cell proliferation and protection against apoptotic death. Through its diverse RNA functions, nucleolin is increasingly implicated in pathological processes, particularly cancer and viral infection. Here, we review the RNA-binding activities of nucleolin, its influence on gene expression patterns, and its impact upon diseases. We also discuss the rising interest in targeting nucleolin therapeutically.
RNA biology 06/2012; 9(6):799-808. · 5.56 Impact Factor
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Kotb Abdelmohsen,
Subramanya Srikantan,
Kumiko Tominaga,
Min-Ju Kang,
Yael Yaniv,
Jennifer L Martindale,
Xiaoling Yang,
Sung-Soo Park,
Kevin G Becker,
Murugan Subramanian,
Stuart Maudsley,
Ashish Lal, Myriam Gorospe
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ABSTRACT: The microRNA miR-519 robustly inhibits cell proliferation, in turn triggering senescence and decreasing tumor growth. However, the molecular mediators of miR-519-elicited growth inhibition are unknown. Here, we systematically investigated the influence of miR-519 on gene expression profiles leading to growth cessation in HeLa human cervical carcinoma cells. By analyzing miR-519-triggered changes in protein and mRNA expression patterns and by identifying mRNAs associated with biotinylated miR-519, we uncovered two prominent subsets of miR-519-regulated mRNAs. One subset of miR-519 target mRNAs encoded DNA maintenance proteins (including DUT1, EXO1, RPA2, and POLE4); miR-519 repressed their expression and increased DNA damage, in turn raising the levels of the cyclin-dependent kinase (cdk) inhibitor p21. The other subset of miR-519 target mRNAs encoded proteins that control intracellular calcium levels (notably, ATP2C1 and ORAI1); their downregulation by miR-519 aberrantly elevated levels of cytosolic [Ca(2+)] storage in HeLa cells, similarly increasing p21 levels in a manner dependent on the Ca(2+)-activated kinases CaMKII and GSK3β. The rises in levels of DNA damage, the Ca(2+) concentration, and p21 levels stimulated an autophagic phenotype in HeLa and other human carcinoma cell lines. As a consequence, ATP levels increased, and the level of activity of the AMP-activated protein kinase (AMPK) declined, further contributing to the elevation in the abundance of p21. Our results indicate that miR-519 promotes DNA damage, alters Ca(2+) homeostasis, and enhances energy production; together, these processes elevate the expression level of p21, promoting growth inhibition and cell survival.
Molecular and cellular biology 04/2012; 32(13):2530-48. · 6.06 Impact Factor
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Eun Kyung Lee,
Wook Kim,
Kumiko Tominaga,
Jennifer L Martindale,
Xiaoling Yang,
Sarah S Subaran,
Olga D Carlson,
Evi M Mercken,
Rohit N Kulkarni,
Wado Akamatsu,
Hideyuki Okano,
Nora I Perrone-Bizzozero,
Rafael de Cabo,
Josephine M Egan, Myriam Gorospe
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ABSTRACT: Although expression of the mammalian RNA-binding protein HuD was considered to be restricted to neurons, we report that HuD is present in pancreatic β cells, where its levels are controlled by the insulin receptor pathway. We found that HuD associated with a 22-nucleotide segment of the 5' untranslated region (UTR) of preproinsulin (Ins2) mRNA. Modulating HuD abundance did not alter Ins2 mRNA levels, but HuD overexpression decreased Ins2 mRNA translation and insulin production, and conversely, HuD silencing enhanced Ins2 mRNA translation and insulin production. Following treatment with glucose, HuD rapidly dissociated from Ins2 mRNA and enabled insulin biosynthesis. Importantly, HuD-knockout mice displayed higher insulin levels in pancreatic islets, while HuD-overexpressing mice exhibited lower insulin levels in islets and in plasma. In sum, our results identify HuD as a pivotal regulator of insulin translation in pancreatic β cells.
Molecular cell 02/2012; 45(6):826-35. · 14.61 Impact Factor
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ABSTRACT: Senescence represents a state of indefinite growth arrest in cells that have reached the end of their replicative life span, have become damaged, or express aberrant levels of cancer-related proteins. While senescence is widely considered to represent a tumor-suppressive mechanism, the accumulation of senescent cells in tissues of older organisms is believed to underlie age-associated losses in physiologic function and age-related diseases. With the emergence of microRNAs (miRNAs) as a major class of molecular regulators of senescence, we review the transcriptional and post-transcriptional factors that control senescence-associated microRNA biosynthesis. Focusing on their enhancement or repression of senescence, we describe the transcription factors that govern the synthesis of primary (pri-)miRNAs, the proteins that control the nuclear processing of pri-miRNAs into precursor (pre-)miRNAs, including RNA editing enzymes, RNases, and RNA helicases, and the cytoplasmic proteins that affect the final processing of pre-miRNAs into mature miRNAs. We discuss how miRNA biogenesis proteins promote or inhibit senescence, and thus influence the senescent phenotype that affects normal tissue function and pathology.
Ageing research reviews 01/2012; 11(4):491-500. · 5.62 Impact Factor
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ABSTRACT: There is extensive evidence that posttranscriptional mechanisms of gene regulation, such as mRNA turnover, critically affect the patterns of expressed mRNAs. Conventional microarray analysis measures steady-state messenger RNA (mRNA) levels, which represents the dynamic balance between new transcription and mRNA degradation. Accordingly, only de novo transcription can accurately reflect the temporal and spatial events of transcriptional regulation. In this chapter, we describe a recently reported method to study transcription systematically. It involves the genome-wide labeling of nascent transcripts using nonradioactive modified nucleotides, their isolation for amplification, and their hybridization and analysis using commercial microarrays.
Methods in molecular biology (Clifton, N.J.) 01/2012; 809:505-17.
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ABSTRACT: The cytoplasmic events that control mammalian gene expression, primarily mRNA stability and translation, potently influence the cellular response to internal and external signals. The ubiquitous RNA-binding protein (RBP) HuR is one of the best-studied regulators of cytoplasmic mRNA fate. Through its post-transcriptional influence on specific target mRNAs, HuR can alter the cellular response to proliferative, stress, apoptotic, differentiation, senescence, inflammatory and immune stimuli. In light of its central role in important cellular functions, HuR's role in diseases in which these responses are aberrant is increasingly appreciated. Here, we review the mechanisms that control HuR function, its influence on target mRNAs, and how impairment in HuR-governed gene expression programs impact upon different disease processes. We focus on HuR's well-recognized implication in cancer and chronic inflammation, and discuss emerging studies linking HuR to cardiovascular, neurological, and muscular pathologies. We also discuss the progress, potential, and challenges of targeting HuR therapeutically.
Frontiers in Bioscience 01/2012; 17:189-205. · 3.52 Impact Factor
