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Frontiers in Aging Neuroscience 2022Alzheimer's disease (AD) is a heterogeneous degenerative disorder of the brain that is on the rise worldwide. One of the critical processes that might be disturbed in AD...
Alzheimer's disease (AD) is a heterogeneous degenerative disorder of the brain that is on the rise worldwide. One of the critical processes that might be disturbed in AD is gene expression regulation. Tristetraprolin (TTP) and RC3H1 gene (ROQUIN) are two RNA-binding proteins (RBPs) that target AU-rich elements (AREs) and constitutive decay elements (CDEs), respectively. TTP and ROQUIN, members of the CCCH zinc-finger protein family, have been demonstrated to fine-tune numerous inflammatory factors. In addition, miR-16 has distinct characteristics and may influence the target mRNA through the ARE site. Interestingly, BDNF mRNA has ARE sites in the 3' untranslated region (UTR) and can be targeted by regulatory factors, such as TTP and miR-16 on MRE sequences, forming BDNF/miR-16/TTP regulatory axis. A number of two microarray datasets were downloaded, including information on mRNAs (GSE106241) and miRNAs (GSE157239) from individuals with AD and corresponding controls. R software was used to identify BDNF, TTP, ROQUIN, and miR-16 expression levels in temporal cortex (TC) tissue datasets. Q-PCR was also used to evaluate the expression of these regulatory factors and the expression of BDNF in the blood of 50 patients with AD and 50 controls. Bioinformatic evaluation showed that TTP and miR-16 overexpression might act as post-transcriptional regulatory factors to control BDNF expression in AD in TC samples. Instead, this expression pattern was not found in peripheral blood samples from patients with AD compared to normal controls. ROQUIN expression was increased in the peripheral blood of patients with AD. Hsa-miR-16-5p levels did not show significant differences in peripheral blood samples. Finally, it was shown that TTP and BDNF, based on evaluating the receiver operating characteristic (ROC), effectively identify patients with AD from healthy controls. This study could provide a new perspective on the molecular regulatory processes associated with AD pathogenic mechanisms linked to the BDNF growth factor, although further research is needed on the possible roles of these factors in AD.
PubMed: 36016853
DOI: 10.3389/fnagi.2022.933019 -
Biochimica Et Biophysica Acta 2013Changes in mRNA stability and translation are critical control points in the regulation of gene expression, particularly genes encoding growth factors, inflammatory... (Review)
Review
Changes in mRNA stability and translation are critical control points in the regulation of gene expression, particularly genes encoding growth factors, inflammatory mediators, and proto-oncogenes. Adenosine and uridine (AU)-rich elements (ARE), often located in the 3' untranslated regions (3'UTR) of mRNAs, are known to target transcripts for rapid decay. They are also involved in the regulation of mRNA stability and translation in response to extracellular cues. This review focuses on one of the best characterized ARE binding proteins, tristetraprolin (TTP), the founding member of a small family of CCCH tandem zinc finger proteins. In this survey, we have reviewed the current status of TTP interactions with mRNA and proteins, and discussed current thinking about TTP's mechanism of action to promote mRNA decay. We also review the proposed regulation of TTP's functions by phosphorylation. Finally, we have discussed emerging evidence for TTP operating as a translational regulator. This article is part of a Special Issue entitled: RNA Decay mechanisms.
Topics: 3' Untranslated Regions; AU Rich Elements; Base Sequence; Cell Line; Gene Expression Regulation; Humans; Molecular Sequence Data; Protein Biosynthesis; RNA Stability; RNA, Messenger; Tristetraprolin; Tumor Necrosis Factor-alpha; Zinc Fingers
PubMed: 23428348
DOI: 10.1016/j.bbagrm.2013.02.003 -
Cancer Epidemiology, Biomarkers &... Mar 2019Inflammation is linked to prostate cancer progression and is mediated by NF-κB. Tristetraprolin is a key node of NF-κB activation and we investigated its biological...
BACKGROUND
Inflammation is linked to prostate cancer progression and is mediated by NF-κB. Tristetraprolin is a key node of NF-κB activation and we investigated its biological and prognostic role in lethal prostate cancer.
METHODS
assays assessed the function of tristetraprolin and the association between low mRNA tristetraprolin levels and lethal prostate cancer (metastatic disease or death) was assessed across independent prostatectomy cohorts: (i) nested case-control studies from Health Professionals Follow-up Study and Physicians' Health Study, and (ii) prostatectomy samples from Cleveland Clinic, Mayo Clinic, Johns Hopkins and Memorial Sloan Kettering Cancer Center. Tristetraprolin expression levels in prostatectomy samples from patients with localized disease and biopsies of metastatic castration-resistant prostate cancer (mCRPC) were assessed in a Cornell University cohort.
RESULTS
tristetraprolin expression was inversely associated with NF-κB-controlled genes, proliferation, and enzalutamide sensitivity. Men with localized prostate cancer and lower quartile of tumor tristetraprolin expression had a significant, nearly two-fold higher risk of lethal prostate cancer after adjusting for known clinical and histologic prognostic features (age, RP Gleason score, T-stage). Tristetraprolin expression was also significantly lower in mCRPC compared with localized prostate cancer.
CONCLUSIONS
Lower levels of tristetraprolin in human prostate cancer prostatectomy tissue are associated with more aggressive prostate cancer and may serve as an actionable prognostic and predictive biomarker.
IMPACT
There is a clear need for improved biomarkers to identify patients with localized prostate cancer in need of treatment intensification, such as adjuvant testosterone suppression, or treatment de-intensification, such as active surveillance. Tristetraprolin levels may serve as informative biomarkers in localized prostate cancer.
Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Case-Control Studies; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Prostatectomy; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Survival Rate; Tristetraprolin
PubMed: 30420441
DOI: 10.1158/1055-9965.EPI-18-0667 -
The International Journal of... Jan 2018Tristetraprolin (TTP) is an RNA-destabilizing protein that exerts profound anti-inflammatory effects by inhibiting the expression of tumour necrosis factor and many... (Review)
Review
Tristetraprolin (TTP) is an RNA-destabilizing protein that exerts profound anti-inflammatory effects by inhibiting the expression of tumour necrosis factor and many other inflammatory mediators. The mitogen-activated protein kinase (MAPK) p38 signaling pathway controls the strength and duration of inflammatory responses by regulating both the expression and function of TTP. The kinase MK2 (MAPK activated kinase 2) is activated by MAPK p38, and in turn phosphorylates TTP at two critical serine residues. One consequence of these phosphorylations is the protection of TTP from proteasome-mediated degradation. Another consequence is the loss of mRNA destabilizing activity. The control of TTP expression and function by the MAPK p38 pathway provides an elegant mechanism for coupling the on and off phases of inflammatory responses, and dictating the precise kinetics of expression of individual inflammatory mediators.
Topics: Animals; Enzyme Activation; Gene Expression Regulation; Humans; Immune System; Inflammation; Intracellular Signaling Peptides and Proteins; MAP Kinase Signaling System; Models, Immunological; Phosphorylation; Proteasome Endopeptidase Complex; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Proteolysis; Tristetraprolin; p38 Mitogen-Activated Protein Kinases
PubMed: 29128684
DOI: 10.1016/j.biocel.2017.11.003 -
Wiley Interdisciplinary Reviews. RNA 2011Adenylate- and uridylate-rich element (ARE) motifs are cis-acting elements present in the 3′ untranslated region of mRNA transcripts that encode many inflammation- and... (Review)
Review
Adenylate- and uridylate-rich element (ARE) motifs are cis-acting elements present in the 3′ untranslated region of mRNA transcripts that encode many inflammation- and cancer-associated genes. The TIS11 family of RNA-binding proteins, composed of tristetraprolin (TTP) and butyrate response factors 1 and 2 (BRF-1 and -2), plays a critical role in regulating the expression of ARE-containing mRNAs. Through their ability to bind and target ARE-containing mRNAs for rapid degradation, this class of RNA-binding proteins serves a fundamental role in limiting the expression of a number of critical genes, thereby exerting anti-inflammatory and anti-cancer effects. Regulation of TIS11 family members occurs on a number of levels through cellular signaling events to control their transcription, mRNA turnover, phosphorylation status, cellular localization, association with other proteins, and proteosomal degradation, all of which impact TIS11 members' ability to promote ARE-mediated mRNA decay along with decay-independent functions. This review summarizes our current understanding of posttranscriptional regulation of ARE-containing gene expression by TIS11 family members and discusses their role in maintaining normal physiological processes and the pathological consequences in their absence.
Topics: Animals; Butyrate Response Factor 1; Humans; Inflammation; Models, Biological; Neoplasms; RNA Stability; Transcription Factors; Tristetraprolin
PubMed: 21278925
DOI: 10.1002/wrna.28 -
Nucleic Acids Research Oct 2022The RNA-binding protein tristetraprolin (TTP) is a potent activator of mRNA decay, specifically for transcripts bearing AU-rich elements (AREs) in their 3'-untranslated...
The RNA-binding protein tristetraprolin (TTP) is a potent activator of mRNA decay, specifically for transcripts bearing AU-rich elements (AREs) in their 3'-untranslated regions. TTP functions as a mediator for mRNA decay by interacting with the decay machinery and recruiting it to the target ARE-mRNA. In this study, we report a weak, but direct interaction between TTP and the human decapping enzyme DCP2, which impacts the stability of ARE transcripts. The TTP-DCP2 interaction is unusual as it involves intrinsically disordered regions (IDRs) of both binding partners. We show that the IDR of DCP2 has a propensity for oligomerization and liquid-liquid phase separation in vitro. Binding of TTP to DCP2 leads to its partitioning into phase-separated droplets formed by DCP2, suggesting that molecular crowding might facilitate the weak interaction between the two proteins and enable assembly of a decapping-competent mRNA-protein complex on TTP-bound transcripts in cells. Our studies underline the role of weak interactions in the cellular interaction network and their contribution towards cellular functionality.
Topics: 3' Untranslated Regions; Endoribonucleases; Humans; RNA Stability; RNA, Messenger; RNA-Binding Proteins; Tristetraprolin
PubMed: 36130271
DOI: 10.1093/nar/gkac797 -
International Immunology Apr 2017Current studies using knockout mice have revealed that some Cys-Cys-Cys-His (CCCH)-type zinc-finger proteins, namely tristetraprolin (TTP), Roquin and Regnase-1, play... (Review)
Review
Current studies using knockout mice have revealed that some Cys-Cys-Cys-His (CCCH)-type zinc-finger proteins, namely tristetraprolin (TTP), Roquin and Regnase-1, play important roles in the immune system. These proteins are closely associated with the fate of their target RNAs in normal immune responses. However, the functions of many RNA-binding proteins have not been characterized precisely. To understand the molecular mechanisms of RNA metabolism in the immune system, investigation of TTP/Roquin/Regnase-1 might provide new knowledge. In this review, we will discuss the current understanding of these proteins in immune regulation and homeostasis and discuss RNA metabolism in the immune system.
Topics: Animals; Humans; Immune System; Immunity; Immunomodulation; RNA Stability; RNA, Messenger; RNA-Binding Proteins; Ribonucleases; Transcription Factors; Tristetraprolin; Ubiquitin-Protein Ligases
PubMed: 28369485
DOI: 10.1093/intimm/dxx015 -
ELife Mar 2023Tristetraprolin (TTP) is a critical negative immune regulator. It binds AU-rich elements in the untranslated-regions of many mRNAs encoding pro-inflammatory mediators,...
Tristetraprolin (TTP) is a critical negative immune regulator. It binds AU-rich elements in the untranslated-regions of many mRNAs encoding pro-inflammatory mediators, thereby accelerating their decay. A key but poorly understood mechanism of TTP regulation is its timely proteolytic removal: TTP is degraded by the proteasome through yet unidentified phosphorylation-controlled drivers. In this study, we set out to identify factors controlling TTP stability. Cellular assays showed that TTP is strongly lysine-ubiquitinated, which is required for its turnover. A genetic screen identified the ubiquitin E3 ligase HUWE1 as a strong regulator of TTP proteasomal degradation, which we found to control TTP stability indirectly by regulating its phosphorylation. Pharmacological assessment of multiple kinases revealed that HUWE1-regulated TTP phosphorylation and stability was independent of the previously characterized effects of MAPK-mediated S52/S178 phosphorylation. HUWE1 function was dependent on phosphatase and E3 ligase binding sites identified in the TTP C-terminus. Our findings indicate that while phosphorylation of S52/S178 is critical for TTP stabilization at earlier times after pro-inflammatory stimulation, phosphorylation of the TTP C-terminus controls its stability at later stages.
Topics: Phosphorylation; Tristetraprolin; Ubiquitin-Protein Ligases; Proteolysis; Ubiquitin; RNA Stability
PubMed: 36961408
DOI: 10.7554/eLife.83159 -
Cancer Medicine Jan 2021Bladder cancer (BCa) is a common malignant tumor of urinary system with few treatments, so more useful therapeutic targets are still needed. Antitumor effects of...
Bladder cancer (BCa) is a common malignant tumor of urinary system with few treatments, so more useful therapeutic targets are still needed. Antitumor effects of tristetraprolin (TTP) have been explored in many type tumors, but its roles in bladder cancer are still unknown until now. In this study, public expression profiles and tissue microarray analysis showed that TTP mRNA and protein levels decreased in BCa relative to the normal bladder tissue. To explore biological functions of TTP in BCa, 488 TTP target genes, which could be both suppressed and bound by TTP, were identified by comprehensively analyzing publicly available high-throughput data obtained from Gene Expression Omnibus (GEO). Gene enrichment analysis showed that these genes were enriched in pathways such as cell cycle, epithelial to mesenchymal transition (EMT), and Wnt signaling. Clustering analysis and gene set variation analysis indicated that patients with high expression of TTP target genes had poorer prognosis and stronger tumor proliferation ability relative to the BCa patients with low expression of TTP target genes. In vitro experiments validated that TTP could suppress proliferation, migration, and invasiveness of BCa cells. And TTP could suppress mRNA expression of cyclin-dependent kinase 1 (CDK1) in BCa cells by target its 3' UTR. Then, we identified a new small double-stranded RNA (dsRNA) named dsTTP-973 which could increase TTP expression in BCa cells, in vivo and in vitro experiments revealed that dsTTP-973 could suppress aggressiveness of BCa. In conclusion, TTP played a role of tumor suppressor gene in BCa like other tumors, and its dsRNA named dsTTP-973 could induce TTP expression in BCa and suppress aggressiveness of BCa. With the help of materials science, dsTTP-973 may become a potential treatment for BCa in the future.
Topics: Animals; CDC2 Protein Kinase; Cell Line, Tumor; Cell Movement; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Genetic Therapy; Humans; Male; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Neoplasm Invasiveness; RNA, Double-Stranded; Tristetraprolin; Tumor Suppressor Proteins; Urinary Bladder Neoplasms; Wnt Signaling Pathway; Xenograft Model Antitumor Assays; Mice
PubMed: 33259133
DOI: 10.1002/cam4.3622 -
Cellular and Molecular Gastroenterology... 2021Tristetraprolin (TTP) is a key post-transcriptional regulator of inflammatory and oncogenic transcripts. Accordingly, TTP was reported to act as a tumor suppressor in...
BACKGROUND & AIMS
Tristetraprolin (TTP) is a key post-transcriptional regulator of inflammatory and oncogenic transcripts. Accordingly, TTP was reported to act as a tumor suppressor in specific cancers. Herein, we investigated how TTP contributes to the development of liver inflammation and fibrosis, which are key drivers of hepatocarcinogenesis, as well as to the onset and progression of hepatocellular carcinoma (HCC).
METHODS
TTP expression was investigated in mouse/human models of hepatic metabolic diseases and cancer. The role of TTP in nonalcoholic steatohepatitis and HCC development was further examined through in vivo/vitro approaches using liver-specific TTP knockout mice and a panel of hepatic cancer cells.
RESULTS
Our data demonstrate that TTP loss in vivo strongly restrains development of hepatic steatosis and inflammation/fibrosis in mice fed a methionine/choline-deficient diet, as well as HCC development induced by the carcinogen diethylnitrosamine. In contrast, low TTP expression fostered migration and invasion capacities of in vitro transformed hepatic cancer cells likely by unleashing expression of key oncogenes previously associated with these cancerous features. Consistent with these data, TTP was significantly down-regulated in high-grade human HCC, a feature further correlating with poor clinical prognosis. Finally, we uncover hepatocyte nuclear factor 4 alpha and early growth response 1, two key transcription factors lost with hepatocyte dedifferentiation, as key regulators of TTP expression.
CONCLUSIONS
Although TTP importantly contributes to hepatic inflammation and cancer initiation, its loss with hepatocyte dedifferentiation fosters cancer cells migration and invasion. Loss of TTP may represent a clinically relevant biomarker of high-grade HCC associated with poor prognosis.
Topics: Animals; Carcinogenesis; Carcinoma, Hepatocellular; Cell Line, Tumor; Datasets as Topic; Diethylnitrosamine; Down-Regulation; Female; Gene Expression Regulation, Neoplastic; Hepatocytes; Humans; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Neoplasms, Experimental; Male; Mice; Non-alcoholic Fatty Liver Disease; Primary Cell Culture; Prognosis; RNA-Seq; Survival Analysis; Tristetraprolin
PubMed: 32987153
DOI: 10.1016/j.jcmgh.2020.09.012