-
Nicotinic stimulation induces Tristetraprolin over-production and attenuates inflammation in muscle.Biochimica Et Biophysica Acta Feb 2012Cholinergic signaling suppresses inflammation in blood and brain and attenuates apoptosis in other tissues, but whether it blocks inflammation in skeletal muscle under...
Cholinergic signaling suppresses inflammation in blood and brain and attenuates apoptosis in other tissues, but whether it blocks inflammation in skeletal muscle under toxicant exposure, injuries and diseases remained unexplored. Here, we report nicotinic attenuation of inflammation and alteration of apoptotic protein expression pattern in murine muscle tissue and cultured myotubes, involving the RNA-binding protein, Tristetraprolin, and the anti-apoptotic protein, Mcl-1. In muscles and C2C12 myotubes, cholinergic excitation by exposure to nicotine or the organophosphorous pesticide, Paraoxon, induced Tristetraprolin overproduction while reducing pro-inflammatory transcripts such as IL-6, CXCL1 (KC) and CCL2 (MCP-1). Furthermore, nicotinic excitation under exposure to the bacterial endotoxin LPS attenuated over-expression of the CCL2 and suppressed the transcriptional activity of NF-ĸB and AP-1. Tristetraprolin was essential for this anti-inflammatory effect of nicotine in basal conditions. However, its knockdown also impaired the pro-inflammatory response to LPS. Finally, in vivo administration of Paraoxon or recombinant Acetylcholinesterase, leading respectively to either gain or loss of cholinergic signaling, modified muscle expression of key mRNA processing factors and several of their apoptosis-related targets. Specifically, cholinergic imbalances enhanced the kinase activators of the Serine-Arginine splicing kinases, Clk1 and Clk3. Moreover, Paraoxon raised the levels of the anti-apoptotic protein, Mcl-1, through a previously unrecognized polyadenylation site selection mechanism, producing longer, less stable Mcl-1 mRNA transcripts. Together, our findings demonstrate that in addition to activating muscle function, acetylcholine regulates muscle inflammation and cell survival, and point to Tristetraprolin and the choice of Mcl-1 mRNA polyadenylation sites as potential key players in muscle reactions to insults.
Topics: Animals; Apoptosis; Cell Line; Cholinesterase Inhibitors; Cytokines; Gene Expression Profiling; Inflammation; Male; Mice; Microarray Analysis; Muscle, Skeletal; Myeloid Cell Leukemia Sequence 1 Protein; Nicotine; Nicotinic Agonists; Paraoxon; Proto-Oncogene Proteins c-bcl-2; Tristetraprolin
PubMed: 22093924
DOI: 10.1016/j.bbamcr.2011.11.001 -
Frontiers in Pharmacology 2021To observe and evaluate the correlation between single-nucleotide polymorphisms (SNPs) and messenger RNA (mRNA) level related to tristetraprolin (TTP) in Chinese...
To observe and evaluate the correlation between single-nucleotide polymorphisms (SNPs) and messenger RNA (mRNA) level related to tristetraprolin (TTP) in Chinese rheumatoid arthritis (RA). TapMan SNP was used for genotyping analysis in 580 RA patients and 554 healthy people. Association between gene polymorphisms (rs251864 and rs3746083) and RA was obtained. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) technology was applied for the detection of TTP mRNA level in peripheral blood mononuclear cells (PBMCs) in 36 RA patients and 37 healthy people. We observed that the allele T of rs3746083 increased RA susceptibility ( = 0.019). A significant difference was found under the dominant model of rs3746083 ( = 0.037). Further analysis showed the allele distribution of rs3746083 was nominally correlated with RF phenotype of RA patients ( = 0.045). Nevertheless, the association between rs251864 and the incidence of RA was no statistically significant ( > 0.05). The TTP expression level in PBMCs of RA patients was significantly reduced ( < 0.001). In conclusion, the results of this experiment support that TTP may be involved in the pathogenesis of RA.
PubMed: 34539409
DOI: 10.3389/fphar.2021.728015 -
PloS One 2017To reveal the effect of p53-tristetraprolin-stathmin-1 signaling on trophoblasts and recurrent spontaneous abortion (RSA).
PROBLEM
To reveal the effect of p53-tristetraprolin-stathmin-1 signaling on trophoblasts and recurrent spontaneous abortion (RSA).
METHOD OF STUDY
Stathmin-1 (STMN1), p53, and tristetraprolin (TTP) expression in paraffin-embedded villus tissue was determined using immunohistochemistry. HTR-8/SVneo cells were treated with doxorubicin to activate p53; STMN1 and TTP levels were detected by quantitative reverse transcription-PCR and western blotting. Western blotting and immunofluorescence were used to investigate STMN1 expression after TTP overexpression or knockdown in HTR-8 cells.
RESULTS
STMN1 was downregulated and p53 was upregulated in the villus tissue from patients with RSA. Doxorubicin decreased STMN1 expression but enhanced TTP expression in HTR-8 cells. In vitro, TTP overexpression inhibited STMN1 production; TTP knockdown promoted it. TTP downregulated STMN1 expression in trophoblasts by directly binding its 3' untranslated region.
CONCLUSIONS
TTP modulates trophoblast function and interacts with STMN1 and p53, and is related to pregnancy outcomes.
Topics: Abortion, Spontaneous; Adult; Blotting, Western; Cell Line; Doxorubicin; Female; Fluorescent Antibody Technique; Humans; Recurrence; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Stathmin; Tristetraprolin; Trophoblasts; Tumor Suppressor Protein p53; Young Adult
PubMed: 28658321
DOI: 10.1371/journal.pone.0179852 -
Biochimica Et Biophysica Acta.... Nov 2022Despite the efficacy of trastuzumab in treating HER2-positive breast cancer patients, a significant proportion of patients relapse after treatment. The role of C-X-C...
Despite the efficacy of trastuzumab in treating HER2-positive breast cancer patients, a significant proportion of patients relapse after treatment. The role of C-X-C chemokine receptor type 4 (CXCR4) in trastuzumab resistance was studied only in cell lines and the underlying mechanisms remain largely unclear. This study investigated the role of CXCR4 in trastuzumab resistance in breast cancer patients and explored the possible underlying mechanisms. The study was performed retrospectively on tissue samples from 62 breast cancer patients including 42 who were treated with trastuzumab and chemotherapy and 20 who received chemotherapy alone in adjuvant setting. Expression levels of CXCR4 and its regulators hypoxia-inducible factor 1-alpha (HIF-1α), tristetraprolin (TTP), human antigen R (HuR), itchy E3 ubiquitin protein ligase (ITCH), miR-302a and miR-494 were determined and their associations with tumor recurrence and disease-free survival were analyzed. In trastuzumab-treated patients, high CXCR4 expression was associated with recurrence and was an independent predictor of progression risk after therapy. CXCR4 correlated positively with its transcriptional regulator, HIF-1α, and negatively with its post-translational regulator, ITCH. HIF-1α, HuR and ITCH were significantly associated with clinical outcome. In chemotherapy-treated patients, neither CXCR4 nor any of its regulators were associated with recurrence or predicted disease progression risk after chemotherapy. In conclusion, this study suggests a potential role for CXCR4 in recurrence after trastuzumab-based therapy in human breast cancer that could be mediated, at least in part, by hypoxia and/or decreased ubiquitination. These findings highlight the potential utility of CXCR4 as a promising target for enhancing trastuzumab therapeutic outcome.
Topics: Breast Neoplasms; Female; Humans; Hypoxia-Inducible Factor 1; MicroRNAs; Receptors, CXCR4; Retrospective Studies; Trastuzumab; Tristetraprolin; Ubiquitin-Protein Ligases
PubMed: 35985446
DOI: 10.1016/j.bbadis.2022.166520 -
Molecular Phylogenetics and Evolution Jan 2016In most mammals, the Zfp36 gene family consists of three conserved members, with a fourth member, Zfp36l3, present only in rodents. The ZFP36 proteins regulate...
In most mammals, the Zfp36 gene family consists of three conserved members, with a fourth member, Zfp36l3, present only in rodents. The ZFP36 proteins regulate post-transcriptional gene expression at the level of mRNA stability in organisms from humans to yeasts, and appear to be expressed in all major groups of eukaryotes. In Mus musculus, Zfp36l3 expression is limited to the placenta and yolk sac, and is important for overall fecundity. We sequenced the Zfp36l3 gene from more than 20 representative species, from members of the Muridae, Cricetidae and Nesomyidae families. Zfp36l3 was not present in Dipodidae, or any families that branched earlier, indicating that this gene is exclusive to the Muroidea superfamily. We provide evidence that Zfp36l3 arose by retrotransposition of an mRNA encoded by a related gene, Zfp36l2 into an ancestral rodent X chromosome. Zfp36l3 has evolved rapidly since its origin, and numerous modifications have developed, including variations in start codon utilization, de novo intron formation by mechanisms including a nested retrotransposition, and the insertion of distinct repetitive regions. One of these repeat regions, a long alanine rich-sequence, is responsible for the full-time cytoplasmic localization of Mus musculus ZFP36L3. In contrast, this repeat sequence is lacking in Peromyscus maniculatus ZFP36L3, and this protein contains a novel nuclear export sequence that controls shuttling between the nucleus and cytosol. Zfp36l3 is an example of a recently acquired, rapidly evolving gene, and its various orthologues illustrate several different mechanisms by which new genes emerge and evolve.
Topics: Animals; Cell Nucleus; Evolution, Molecular; Female; Humans; Introns; Muridae; Peromyscus; Phylogeny; Placenta; Pregnancy; Proteins; RNA, Messenger; Repetitive Sequences, Nucleic Acid; Retroelements; Rodentia; Tristetraprolin
PubMed: 26493225
DOI: 10.1016/j.ympev.2015.10.016 -
International Journal of Molecular... Sep 2020AU-rich element-binding proteins (AUBPs) represent important post-transcriptional regulators of gene expression. AUBPs can bind to the AU-rich elements present in the... (Review)
Review
AU-rich element-binding proteins (AUBPs) represent important post-transcriptional regulators of gene expression. AUBPs can bind to the AU-rich elements present in the 3'-UTR of more than 8% of all mRNAs and are thereby able to control the stability and/or translation of numerous target mRNAs. The regulation of the stability and the translation of mRNA transcripts by AUBPs are highly complex processes that occur through multiple mechanisms depending on the cell type and the cellular context. While AUBPs have been shown to be involved in inflammatory processes and the development of various cancers, their important role and function in the development of chronic metabolic and inflammatory fatty liver diseases (FLDs), as well as in the progression of these disorders toward cancers such as hepatocellular carcinoma (HCC), has recently started to emerge. Alterations of either the expression or activity of AUBPs are indeed significantly associated with FLDs and HCC, and accumulating evidence indicates that several AUBPs are deeply involved in a significant number of cellular processes governing hepatic metabolic disorders, inflammation, fibrosis, and carcinogenesis. Herein, we discuss our current knowledge of the roles and functions of AUBPs in liver diseases and cancer. The relevance of AUBPs as potential biomarkers for different stages of FLD and HCC, or as therapeutic targets for these diseases, are also highlighted.
Topics: 3' Untranslated Regions; Animals; Carcinoma, Hepatocellular; Humans; Inflammation; Liver Neoplasms; RNA Processing, Post-Transcriptional; RNA, Messenger
PubMed: 32932781
DOI: 10.3390/ijms21186648 -
Journal of Translational Medicine May 2022Prostatic cancer (PCa) is one of the most common malignant tumors in men worldwide. Emerging evidence indicates significance of hypoxia and immunity in PCa invasion and...
Identification of ISG15 and ZFP36 as novel hypoxia- and immune-related gene signatures contributing to a new perspective for the treatment of prostate cancer by bioinformatics and experimental verification.
BACKGROUND
Prostatic cancer (PCa) is one of the most common malignant tumors in men worldwide. Emerging evidence indicates significance of hypoxia and immunity in PCa invasion and metastasis. This study aimed to develop a hypoxia- and immune-related gene risk signature and explore the molecular mechanisms to formulate a better prognostic tool for PCa patients.
METHODS
The hypoxia and immune scores of all PCa patients in The Cancer Genome Atlas (TCGA) dataset were calculated via the maximally selected rank statistics method and the ESTIMATE algorithm. From common genes identified overlapping hypoxia- and immune-related differentially expressed genes (DE-HRGs and DE-IRGs), a hypoxia- and immune-related gene risk signature was developed utilizing univariate and multivariate Cox regression analyses, and validated in the Memorial Sloan Kettering Cancer Centre (MSKCC) database. The immune cell infiltration level of PCa samples were evaluated with ssGSEA algorithm. Differential expression of prognostic genes was evidenced by immunohistochemistry and western blot (WB) in paired PCa samples. Expression levels of these genes and their variations under regular and hypoxic conditions were examined in cell lines. The functional effects of the prognostic gene on PCa cells were examined by wound healing and transwell assays.
RESULTS
A hypoxia- and immune-related gene risk signature constructed by ISG15 and ZFP36 displays significant predictive potency, with higher risk score representing worse survival. A nomogram based on independent prognostic factors including the risk score and Gleason score exhibited excellent clinical value in the survival prediction of PCa. Infiltration levels of eosinophils, neutrophils, Tcm, Tem, TFH, Th1 cells, and Th17 cells were significantly lower in the high-risk group. Conversely, aDC, pDC, T helper cells, and Tregs were significantly higher. Additionally, the two prognostic genes were closely correlated with the tumor-infiltrating immune cell subset in PCa progression. RT-qPCR and WB presented higher and lower expression of ISG15 and ZFP36 in PCa cells, respectively. They were correspondingly increased and decreased in PCa cells under hypoxic conditions. Wound healing and transwell assays showed that over-expression of ISG15 promoted the migration and invasion of PCa cells.
CONCLUSION
Our study identified a novel hypoxia- and immune-related gene signature, contributing a new perspective to the treatment of PCa.
Topics: Biomarkers, Tumor; Computational Biology; Cytokines; Gene Expression Profiling; Humans; Hypoxia; Male; Prostatic Neoplasms; Tristetraprolin; Ubiquitins
PubMed: 35538543
DOI: 10.1186/s12967-022-03398-4 -
European Review For Medical and... Jan 2018This study sought to explore HuR, Thrombotic Thrombocytopenic Purpura (TTP), and microRNA 133b (miR-133b) expression levels in non-small cell lung cancer (NSCLC)...
OBJECTIVE
This study sought to explore HuR, Thrombotic Thrombocytopenic Purpura (TTP), and microRNA 133b (miR-133b) expression levels in non-small cell lung cancer (NSCLC) patients and assess the relationship of expression with disease prognosis.
PATIENTS AND METHODS
One hundred and ten paraffin-embedded and 33 fresh flash-frozen NSCLC samples, together with matched tumor adjacent normal tissue controls, were collected from patients between January 2013 and July 2015 in Yidu Central Hospital of Weifang. Twenty-nine patients provided both paraffin-embedded and fresh frozen tissues. HuR and TTP protein expression levels were measured in 110 paraffin-embedded tumors and matched controls using immunohistochemistry, while miR-133b levels were measured using Real-time fluorescent quantitative PCR.
RESULTS
Follow-up parameters included treatment response, relapse events, post-relapse treatment, disease free survival (DFS), and overall survival (OS). HuR expression was significantly different between tumor and matched controls (p < 0.0001). Cytoplasmic expression levels of HuR and TTP correlated with pTNM staging (p < 0.05). No significant correlation was observed between HuR and TTP expression and other clinical pathological factors (gender, age, tumor size, pathological subtype, differentiation status, lymph node metastasis, distant metastasis, and tumor invasiveness). MiR-133b expression correlated with tumor size (p = 0.015) and differentiation status (p = 0.013) in paraffin-embedded sections, but was only correlated with pTNM staging (p = 0.032) in frozen tissue samples. No significant difference in DFS nor OS was observed between 68 HuR-positive and 42 HuR-negative patients (DFS, Log Rank p = 0.712; OS, Log Rank p = 0.220). However, DFS and OS were significantly different between miR-133b high-expression and low-expression patients (DFS, Log Rank p = 0.048 < 0.05; OS, Log Rank p = 0.025 < 0.05). This indicates that miR-133b levels may have prognostic value.
CONCLUSIONS
HuR expression was negatively correlated with TTP expression in NSCLC tissues. MiR-133b levels were downregulated in normal tissues compared to both paraffin and frozen tumor samples, and correlated with both HuR and TTP expression, which may affect the prognosis of NSCLC patients.
Topics: Adult; Aged; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Down-Regulation; ELAV-Like Protein 1; Female; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Lymphatic Metastasis; Male; MicroRNAs; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Prognosis; Tristetraprolin
PubMed: 29424924
DOI: 10.26355/eurrev_201801_14192 -
The Journal of Biological Chemistry Apr 2017Inflammatory signals induce feedback and feedforward systems that provide temporal control. Although glucocorticoids can repress inflammatory gene expression,... (Review)
Review
Inflammatory signals induce feedback and feedforward systems that provide temporal control. Although glucocorticoids can repress inflammatory gene expression, glucocorticoid receptor recruitment increases expression of negative feedback and feedforward regulators, including the phosphatase, DUSP1, the ubiquitin-modifying enzyme, TNFAIP3, or the mRNA-destabilizing protein, ZFP36. Moreover, glucocorticoid receptor cooperativity with factors, including nuclear factor-κB (NF-κB), may enhance regulator expression to promote repression. Conversely, MAPKs, which are inhibited by glucocorticoids, provide feedforward control to limit expression of the transcription factor IRF1, and the chemokine, CXCL10. We propose that modulation of feedback and feedforward control can determine repression or resistance of inflammatory gene expression toglucocorticoid.
Topics: A549 Cells; Animals; Chemokine CXCL10; Cytokines; Dual Specificity Phosphatase 1; Feedback, Physiological; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Glucocorticoids; Humans; Inflammation; Interferon Regulatory Factor-1; MAP Kinase Signaling System; Mice; NF-kappa B; RNA, Messenger; Receptors, Glucocorticoid; Signal Transduction; Transcription Factor RelA; Tristetraprolin; Tumor Necrosis Factor alpha-Induced Protein 3
PubMed: 28283576
DOI: 10.1074/jbc.R117.777318 -
Cell Death & Disease Aug 2023Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, with high morbidity and mortality worldwide. Although the dysregulation of BARX1 expression...
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, with high morbidity and mortality worldwide. Although the dysregulation of BARX1 expression has been shown to be associated with malignant cancers, including NSCLC, the underlying mechanism remains elusive. In this study, we identified BARX1 as a common differentially expressed gene in lung squamous cell carcinoma and adenocarcinoma. Importantly, we uncovered a novel mechanism behind the regulation of BARX1, in which ZFP36 interacted with 3'UTR of BARX1 mRNA to mediate its destabilization. Loss of ZFP36 led to the upregulation of BARX1, which further promoted the proliferation, migration and invasion of NSCLC cells. In addition, the knockdown of BARX1 inhibited tumorigenicity in mouse xenograft. We demonstrated that BARX1 promoted the malignant phenotypes by transactivating a set of master oncogenes involved in the cell cycle, DNA synthesis and metastasis. Overall, our study provides insights into the mechanism of BARX1 actions in NSCLC and aids a better understanding of NSCLC pathogenesis.
Topics: Animals; Humans; Mice; Adenocarcinoma; Carcinoma, Non-Small-Cell Lung; Homeodomain Proteins; Lung Neoplasms; Oncogenes; Phenotype; Transcription Factors; Tristetraprolin
PubMed: 37587140
DOI: 10.1038/s41419-023-06044-z