HuR is an RNA binding protein with an alleged role in the posttranscriptional activation of inflammatory mRNAs bearing AU-rich elements (AREs). Here, we show that the inducible increase of HuR in murine innate compartments suppresses inflammatory responses in vivo. In macrophages, HuR overexpression induced the translational silencing of specific cytokine mRNAs despite positive or nominal effects on their corresponding turnover. By using a model system of ARE dysfunction, we demonstrate that HuR does not alter the accumulation of target mRNAs in the absence of the destabilizing functions of Tristetraprolin but synergizes with the translational silencer TIA-1 to reduce the translation of cytokine mRNAs. Our data suggest that HuR acts in a pleiotropic fashion in inflammation through its functional interactions with specific mRNA subsets and negative posttranscriptional modules.
HuR is an RNA-binding protein implicated in a diverse array of pathophysiological processes due to its effects on the posttranscriptional regulation of AU-and U-rich mRNAs. Here we reveal HuR's requirement in embryonic development through its genetic ablation. Obligatory HuR-null embryos exhibited a stage retardation phenotype and failed to survive beyond midgestation. By means of conditional transgenesis, we restricted HuR's mutation in either embryonic or endothelial compartments to demonstrate that embryonic lethality is consequent to defects in extraembryonic placenta. HuR's absence impaired the invagination of allantoic capillaries into the chorionic trophoblast layer and the differentiation of syncytiotrophoblast cells that control the morphogenesis and vascularization of the placental labyrinth and fetal support. HuR-null embryos rescued from these placental defects proceeded to subsequent developmental stages but displayed defects in skeletal ossification, fusions in limb elements, and asplenia. By coupling gene expression measurements, data metaanalysis, and HuR-RNA association assays, we identified transcription and growth factor mRNAs controlled by HuR, primarily at the posttranscriptional level, to guide morphogenesis, specification, and patterning. Collectively, our data demonstrate the dominant role of HuR in organizing gene expression programs guiding placental labyrinth morphogenesis, skeletal specification patterns, and splenic ontogeny.
T hymic T cell development involves discrete stages of differentiation, activation, death, and migration aiming to provide a T cell repertoire against invasion while maintaining tolerance to self. Double-negative (DN) 3 progenitors (CD4 Ϫ CD8 Ϫ ) entering the thymic cortex from the bone marrow proceed through four differentiation stages to yield cells competent for antigenic stimulation. In the case of conventional T cells, this is achieved by the somatic recombination of TCR genes, the elimination of aberrant rearrangements, and the association of the TCR-chains with the invariant TCR␣-chain. This pre-TCR complex signals DN cells to expand and become CD4 ϩ CD8 ϩ double-positive (DP) cells (1). DP cells rearrange their TCR␣ locus and progressively express surface TCR␣/ for interaction with MHC-presented Ags on the thymic epithelium. The qualitative and quantitative features of these interactions guide the selection of nonself reacting CD4 ϩ or CD8 ϩ single-positive (SP) thymocytes (2). Nominal or strong autoreactive interactions cause elimination by neglect or negative selection, respectively; moderate interactions lead to positive selection. In parallel, an array of cytokine/ chemokine signals define the thresholds of these interactions and facilitate thymocyte movements from the cortex to the medulla and peripheral blood (3, 4). These staged events require the precise orchestration of gene expression programs governed by genetic, epigenetic, and transcriptional mechanisms.Posttranscriptional mechanisms of mRNA use may also affect thymocyte development because they contribute to as much as 50% of T cell-specific gene expression changes during activation (5). However, the trans-acting factors regulating these changes have not been well studied. Such factors include the RNA-binding proteins (RBPs) that determine mRNA maturation, localization, stability, and translation (6). This type of control is particularly stringent in mRNAs that possess adenylate and/or uridylate-rich elements and frequently encode cytokines, signaling molecules, and oncoproteins (7). Within the selective set of RBPs recognizing adenylate and/or uridylate-rich elements, HuR (or HuA) emerged as a pleiotropic modulator of mRNA use. HuR contains RNA recognition motifs with an affinity for a U-rich motif and it is the only ubiquitous member of the otherwise neuronal Elavl/Hu family (8). HuR shuttles between the nucleus and the cytoplasm via interactions with nuclear export/import adaptor proteins (9). In the cytoplasm, HuR can affect mRNA stability and/or translation (8, 10 -12) via complex interplays with other RBPs, such as hnRNPD/ AUF1, TTP, BRF1 and KSRP, as well as microRNAs (13,14). Recent data suggest that HuR's functions can be controlled by posttranslational modifications like phosphorylation, methylation, and cleavage (15-18). Furthermore, HuR:RNA immunoprecipitations demonstrated that, in vivo, HuR associates with mRNAs that are relevant to a certain cellular response (6,14), suggesting that its functions may vary in a tissue and...
The oncofetal CRD-BP/IMP1 RNA binding protein regulates posttranscriptionally a handful of RNA transcripts, implicated in cell adhesion and invadopodia formation and was recently identified as a target of the b-catenin/Tcf transcription factor that is constitutively activated in colorectal carcinomas (CRCs). The expression of CRD-BP/IMP1 was studied in normal adult intestines and CRCs. In normal mucosa, CRD-BP/IMP1 immunoreactivity was observed in few scattered cells located predominantly at or near the bottom of the crypts, whereas in CRCs the protein was detectable in tumor cells of 50% of the specimens analyzed. CRD-BP/ IMP1 mRNA expression was measured by qRT-PCR in 78 CRCs. Thirty-two (41%) of the specimens were negative or had negligible expression, whereas the remaining forty-six (59%) expressed a wide range of CRD-BP/IMP1 mRNA levels. CRD-BP/IMP1 mRNA expression correlated with that of the putative stem/progenitor cell marker Musashi-1 mRNA (p 5 0. 035). CRD-BP/IMP1 positive tumors metastasized and/or recurred more frequently (p 5 0.001) and its expression defined a group of patients with shorter survival (p 5 0.014). Furthermore, in a multivariate analysis CRD-BP/IMP1 expression was found to be an independent predictor of survival (p 5 0.015). For stage I & II patients, the differences in metastasis/recurrence and survival rates remained significant (p 5 0.001 and 0.033, respectively). These findings indicate that CRD-BP/IMP1 positive tumors exhibit early disease dissemination and unfavorable prognosis. ' 2007 Wiley-Liss, Inc.
The Wnt pathway is abnormally activated in the majority of colorectal cancers, and significant knowledge has been gained in understanding its role in tumor initiation. However, the mechanisms of metastatic outgrowth in colorectal cancer remain a major challenge. We report that autophagy-dependent metabolic adaptation and survival of metastatic colorectal cancer cells is regulated by the target of oncogenic Wnt signaling, homeobox transcription factor PROX1, expressed by a subpopulation of colon cancer progenitor/stem cells. We identify direct PROX1 target genes and show that repression of a pro-apoptotic member of the BCL2 family, BCL2L15, is important for survival of PROX1(+) cells under metabolic stress. PROX1 inactivation after the establishment of metastases prevented further growth of lesions. Furthermore, autophagy inhibition efficiently targeted metastatic PROX1(+) cells, suggesting a potential therapeutic approach. These data identify PROX1 as a key regulator of the transcriptional network contributing to metastases outgrowth in colorectal cancer.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2025 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.