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Molecular Oncology May 2018Tristetraprolin (TTP) is an AU-rich element-binding protein that regulates mRNA stability and plays important roles in cancer. The mechanisms by which TTP is regulated...
Tristetraprolin (TTP) is an AU-rich element-binding protein that regulates mRNA stability and plays important roles in cancer. The mechanisms by which TTP is regulated in breast cancer are poorly understood. Using multiple biochemical approaches, we found that proviral insertion in murine lymphomas 2 (PIM2) is a novel binding partner of TTP. Interestingly, PIM2 decreased TTP protein levels independent of its kinase activity. PIM2 instead targeted TTP protein for degradation via the ubiquitin-proteasome pathway. Furthermore, immunohistochemical staining showed that PIM2 and TTP protein levels were negatively correlated in human breast cancer samples. Indeed, PIM2 overexpression de-repressed TTP-mediated inhibition of breast cancer cell proliferation and migration in vitro and promoted breast tumor xenograft growth in vivo. These findings demonstrate an important role for the PIM2-TTP complex in breast cancer tumorigenesis, suggesting that PIM2 may represent a potential therapeutic target for breast cancer treatment.
Topics: Adult; Animals; Breast Neoplasms; Carcinogenesis; Cell Line; Cell Movement; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Humans; Mice, Nude; Middle Aged; Proteasome Endopeptidase Complex; Protein Binding; Protein Domains; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; RNA, Messenger; Tristetraprolin; Ubiquitin; Zinc Fingers
PubMed: 29570932
DOI: 10.1002/1878-0261.12192 -
Cell Death & Disease Jun 2020Diabetic kidney disease (DKD) is one of the most common complications of diabetes, and the most common cause of end-stage renal disease, for which no effective therapies...
Diabetic kidney disease (DKD) is one of the most common complications of diabetes, and the most common cause of end-stage renal disease, for which no effective therapies are yet available. RNA-binding proteins (RBPs) play a pivotal role in epigenetic regulation; tristetraprolin (TTP) and human antigen R (HuR) competitively bind cytokine mRNAs, exert contrasting effects on RNA stability, and drive inflammation. However, RBPs' roles in diabetes-related glomerulopathy are poorly understood. Herein, we investigated whether TTP and HuR are involved in post-transcriptional regulation of podocytopathic molecules and inflammatory cytokines in DKD. In DKD patients and db/db mice, TTP expression was significantly decreased and HuR expression was increased in glomerular podocytes, concurrent with podocyte injury, histological signs of DKD, and augmented glomerular expression of interleukin (IL)-17 and claudin-1, which are targets of TTP and HuR, as evidenced by RNA immunoprecipitation. In cultured podocytes, exposure to high ambient glucose amplified HuR expression and repressed TTP expression, upregulated IL-17 and claudin-1, and promoted podocyte injury. Thus, TTP hypoactivity or HuR hyperactivity is sufficient and essential to diabetic podocytopathy. Moreover, in silico analysis revealed that several kinases govern phosphorylation and activation of TTP and HuR, and glycogen synthase kinase (GSK)-3β activated both TTP and HuR, which harbor putative GSK-3β consensus phosphorylation motifs. Treatment of db/db mice with a small molecule inhibitor of GSK-3β abrogated the changes in TTP and HuR in glomeruli and mitigated the overexpression of their target genes (IL-17, claudin-1, B7-1, and MCP-1) thus also mitigating proteinuria and DKD pathology. Our study indicates that TTP and HuR are dysregulated in DKD via a GSK-3β-mediated mechanism and play crucial roles in podocyte injury through post-transcriptional regulation of diverse genes. It also provides novel insights into DKD's pathophysiology and identifies potential therapeutic targets.
Topics: Animals; Cells, Cultured; Claudin-1; Diabetic Nephropathies; ELAV-Like Protein 1; Glucose; Glycogen Synthase Kinase 3 beta; Homeostasis; Humans; Inflammation; Interleukin-17; Mice, Inbred C57BL; Models, Biological; Podocytes; Proteinuria; RNA, Messenger; Streptozocin; Thiadiazoles; Tristetraprolin
PubMed: 32487989
DOI: 10.1038/s41419-020-2630-x -
American Journal of Physiology. Renal... Mar 2014The posttranscriptional regulation of gene expression occurs through cis RNA regulatory elements by the action of trans factors, which are represented by noncoding RNAs... (Review)
Review
The posttranscriptional regulation of gene expression occurs through cis RNA regulatory elements by the action of trans factors, which are represented by noncoding RNAs (especially microRNAs) and turnover- and translation-regulatory (TTR) RNA-binding proteins (RBPs). These multifactorial proteins are a group of heterogeneous RBPs primarily implicated in controlling the decay and translation rates of target mRNAs. TTR-RBPs usually shuttle between cellular compartments (the nucleus and cytoplasm) in response to various stimuli and undergo posttranslational modifications such as phosphorylation or methylation to ensure their proper subcellular localization and function. TTR-RBPs are emerging as key regulators of a wide variety of genes influencing kidney physiology and pathology. This review summarizes the current knowledge of TTR-RBPs that influence renal metabolism. We will discuss the role of TTR-RBPs as regulators of kidney ischemia, fibrosis and matrix remodeling, angiogenesis, membrane transport, immunity, vascular tone, hypertension, and acid-base balance as well as anemia, bone mineral disease, and vascular calcification.
Topics: Acid-Base Equilibrium; Aging; Animals; ELAV Proteins; Heterogeneous Nuclear Ribonucleoprotein D0; Heterogeneous-Nuclear Ribonucleoprotein D; Humans; Kidney; MicroRNAs; Neovascularization, Physiologic; Poly(A)-Binding Proteins; Protein Processing, Post-Translational; RNA, Messenger; RNA-Binding Proteins; T-Cell Intracellular Antigen-1; Tristetraprolin; Vascular Calcification; Y-Box-Binding Protein 1
PubMed: 24431206
DOI: 10.1152/ajprenal.00270.2013 -
Arthritis Research & Therapy 2004Tristetraprolin (TTP) is the best-studied member of a small family of three proteins in humans that is characterized by a tandem CCCH zinc finger (TZF) domain with... (Comparative Study)
Comparative Study Review
Tristetraprolin (TTP) is the best-studied member of a small family of three proteins in humans that is characterized by a tandem CCCH zinc finger (TZF) domain with highly conserved sequences and spacing. Although initially discovered as a gene that could be induced rapidly and transiently by the stimulation of fibroblasts with growth factors and mitogens, it is now known that TTP can bind to AU-rich elements in mRNA, leading to the removal of the poly(A) tail from that mRNA and increased rates of mRNA turnover. This activity was discovered after TTP-deficient mice were created and found to have a systemic inflammatory syndrome with severe polyarticular arthritis and autoimmunity, as well as medullary and extramedullary myeloid hyperplasia. The syndrome seemed to be due predominantly to excess circulating tumor necrosis factor-alpha (TNF-alpha), resulting from the increased stability of the TNF-alpha mRNA and subsequent higher rates of secretion of the cytokine. The myeloid hyperplasia might be due in part to increased stability of granulocyte-macrophage colony-stimulating factor (GM-CSF). This review highlights briefly the characteristics of the TTP-deficiency syndrome in mice and its possible genetic modifiers, as well as recent data on the characteristics of the TTP-binding site in the TNF-alpha and GM-CSF mRNAs. Recent structural data on the characteristics of the complex between RNA and one of the TTP-related proteins are reviewed, and used to model the TTP-RNA binding complex. We review the current knowledge of TTP sequence variants in humans and discuss the possible contributions of the TTP-related proteins in mouse physiology and in human monocytes. The TTP pathway of TNF-alpha and GM-CSF mRNA degradation is a possible novel target for anti-TNF-alpha therapies for rheumatoid arthritis, and also for other conditions proven to respond to anti-TNF-alpha therapy.
Topics: Animals; Base Sequence; Binding Sites; Bone Diseases, Developmental; Crosses, Genetic; Epistasis, Genetic; Gene Expression Regulation; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Mice; Mice, Knockout; Models, Molecular; Molecular Sequence Data; Phenotype; Polymorphism, Genetic; Protein Binding; Protein Conformation; RNA, Messenger; Sequence Alignment; Structure-Activity Relationship; Tumor Necrosis Factor-alpha; Zinc Fingers
PubMed: 15535838
DOI: 10.1186/ar1441 -
Cells Aug 2020Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has attracted attention as a potential candidate for cancer therapy. However, many primary cancers...
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has attracted attention as a potential candidate for cancer therapy. However, many primary cancers are resistant to TRAIL, even when combined with standard chemotherapy. The mechanism of TRAIL resistance in cancer cells has not been fully elucidated. The TRAIL death receptor (DR) 3'-untranslated region (3'-UTR) is reported to contain AU-rich elements (AREs) that are important for regulating DR mRNA stability. However, the mechanisms by which DR mRNA stability is determined by its 3'-UTR are unknown. We demonstrate that tristetraprolin (TTP), an ARE-binding protein, has a critical function of regulating DR mRNA stability. DR4 mRNA contains three AREs and DR5 mRNA contains four AREs in 3'-UTR. TTP bound to all three AREs in DR4 and ARE3 in DR5 and enhanced decay of DR4/5 mRNA. TTP overexpression in colon cancer cells changed the TRAIL-sensitive cancer cells to TRAIL-resistant cells, and down-regulation of TTP increased TRAIL sensitivity via DR4/5 expression. Therefore, this study provides a molecular mechanism for enhanced levels of TRAIL DRs in cancer cells and a biological basis for posttranscriptional modification of TRAIL DRs. In addition, TTP status might be a biomarker for predicting TRAIL response when a TRAIL-based treatment is used for cancer.
Topics: Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; RNA Processing, Post-Transcriptional; Receptors, TNF-Related Apoptosis-Inducing Ligand; TNF-Related Apoptosis-Inducing Ligand; Tristetraprolin
PubMed: 32784606
DOI: 10.3390/cells9081851 -
Frontiers in Immunology 2020Non-infectious uveitis, a common cause of blindness in man, is often mediated by autoimmunity, a process in which cytokines play major roles. The biosynthesis and...
Non-infectious uveitis, a common cause of blindness in man, is often mediated by autoimmunity, a process in which cytokines play major roles. The biosynthesis and secretion of pro-inflammatory cytokines are regulated in part by tristetraprolin (TTP), an endogenous anti-inflammatory protein that acts by binding directly to specific sequence motifs in the 3'-untranslated regions of target mRNAs, promoting their turnover, and inhibiting synthesis of their encoded proteins. We recently developed a TTP-overexpressing mouse (TTPΔARE) by deleting an AU-rich element (ARE) instability motif from the TTP mRNA, resulting in increased accumulation of TTP mRNA and protein throughout the animal. Here, we show that homozygous TTPΔARE mice are resistant to the induction of experimental autoimmune uveitis (EAU) induced by interphotoreceptor retinoid-binding protein (IRBP), an established model for human autoimmune (noninfectious) uveitis. Lymphocytes from TTPΔARE mice produced lower levels of the pro-inflammatory cytokines IFN-γ, IL-17, IL-6, and TNFα than wild type (WT) mice. TTPΔARE mice also produced lower titers of antibodies against the uveitogenic protein. In contrast, TTPΔARE mice produced higher levels of the anti-inflammatory cytokine IL-10, and had higher frequencies of regulatory T-cells, which, moreover, displayed a moderately higher per-cell regulatory ability. Heterozygous mice developed EAU and associated immunological responses at levels intermediate between homozygous TTPΔARE mice and WT controls. TTPΔARE mice were able, however, to develop EAU following adoptive transfer of activated WT T-cells specific to IRBP peptide 651-670, and naïve T-cells from TTPΔARE mice could be activated by antibodies to CD3/CD28. Importantly, TTPΔARE antigen presenting cells were significantly less efficient compared to WT in priming naïve T cells, suggesting that this feature plays a major role in the dampened immune responses of the TTPΔARE mice. Our observations demonstrate that elevated systemic levels of TTP can inhibit the pathogenic processes involved in EAU, and suggest the possible use of TTP-based treatments in humans with uveitis and other autoimmune conditions.
Topics: Animals; Autoimmune Diseases; Female; Gene Knock-In Techniques; Male; Mice; Mice, Inbred C57BL; Nervous System Autoimmune Disease, Experimental; Tristetraprolin; Uveitis
PubMed: 33569048
DOI: 10.3389/fimmu.2020.583510 -
Genome Biology Jan 2021Crosstalk between genetic, epigenetic, and immune alterations in upper tract urothelial carcinomas and their role in shaping muscle invasiveness and patient outcome are...
BACKGROUND
Crosstalk between genetic, epigenetic, and immune alterations in upper tract urothelial carcinomas and their role in shaping muscle invasiveness and patient outcome are poorly understood.
RESULTS
We perform an integrative genome- and methylome-wide profiling of diverse non-muscle-invasive and muscle-invasive upper tract urothelial carcinomas. In addition to mutations of FGFR3 and KDM6A, we identify ZFP36L1 as a novel, significantly mutated tumor suppressor gene. Overall, mutations of ZFP36 family genes (ZFP36, ZFP36L1, and ZFP36L2) are identified in 26.7% of cases, which display a high mutational load. Unsupervised DNA methylation subtype classification identifies two epi-clusters associated with distinct muscle-invasive status and patient outcome, namely, EpiC-low and EpiC-high. While the former is hypomethylated, immune-depleted, and enriched for FGFR3-mutated, the latter is hypermethylated, immune-infiltrated, and tightly associated with somatic mutations of SWI/SNF genes.
CONCLUSIONS
Our study delineates for the first time the key role for convergence between genetic and epigenetic alterations in shaping clinicopathological and immune upper tract urothelial carcinoma features.
Topics: Butyrate Response Factor 1; Carcinoma, Transitional Cell; Cell Line, Tumor; DNA Methylation; Epigenomics; Gene Expression Regulation, Neoplastic; Histone Demethylases; Humans; Immunity; Mutation; Receptor, Fibroblast Growth Factor, Type 3; Transcription Factors; Transcriptome; Tristetraprolin; Urinary Bladder Neoplasms
PubMed: 33397444
DOI: 10.1186/s13059-020-02230-w -
Trends in Pharmacological Sciences Oct 2016Members of the tristetraprolin (TTP) family of RNA-binding proteins are found in all major eukaryotic groups. TTP family members, from plants through humans, can bind... (Review)
Review
Members of the tristetraprolin (TTP) family of RNA-binding proteins are found in all major eukaryotic groups. TTP family members, from plants through humans, can bind adenosine-uridine rich elements in target mRNAs with high affinity. In mammalian cells, these proteins then promote deadenylation and decay of target transcripts. Four such proteins are found in mice, of which the best studied is TTP. When the gene encoding TTP is disrupted in mice, the animals develop a severe syndrome of arthritis, autoimmunity, cachexia, dermatitis, and myeloid hyperplasia. Conversely, recent overexpression studies have demonstrated protection against several experimental models of immune inflammatory disease. This endogenous anti-inflammatory protein could serve as the basis for novel approaches to therapy of similar conditions in humans.
Topics: Animals; Anti-Inflammatory Agents; Autoimmune Diseases; Disease Models, Animal; Drug Design; Humans; Inflammation; Mice; RNA, Messenger; Tristetraprolin
PubMed: 27503556
DOI: 10.1016/j.tips.2016.07.002 -
MBio Oct 2023Our findings define a novel role for ZIKV-induced TTP expression in regulating IFNβ/IFNλ production in primary hBMECs and Sertoli cells. These cells comprise key...
Our findings define a novel role for ZIKV-induced TTP expression in regulating IFNβ/IFNλ production in primary hBMECs and Sertoli cells. These cells comprise key physiological barriers subverted by ZIKV to access brain and testicular compartments and serve as reservoirs for persistent replication and dissemination. We demonstrate for the first time that the ARE-binding protein TTP is virally induced and post-transcriptionally regulates IFNβ/IFNλ secretion. In ZIKV-infected hBMEC and Sertoli cells, TTP knockout increased IFNβ/IFNλ secretion, while TTP expression blocked IFNβ/IFNλ secretion. The TTP-directed blockade of IFN secretion permits ZIKV spread and persistence in hBMECs and Sertoli cells and may similarly augment ZIKV spread across IFNλ-protected placental barriers. Our work highlights the importance of post-transcriptional ZIKV regulation of IFN expression and secretion in cells that regulate viral access to protected compartments and defines a novel mechanism of ZIKV-regulated IFN responses which may facilitate neurovirulence and sexual transmission.
Topics: Pregnancy; Male; Female; Humans; Sertoli Cells; Zika Virus; Zika Virus Infection; Tristetraprolin; Placenta; Virus Replication
PubMed: 37707056
DOI: 10.1128/mbio.01742-23 -
Nature Communications Oct 2017IFN-γ-producing cytotoxic T lymphocytes are essential for host defense against viral infection and cancer. Here we show that the RNA-binding tristetraprolin, encoded by...
IFN-γ-producing cytotoxic T lymphocytes are essential for host defense against viral infection and cancer. Here we show that the RNA-binding tristetraprolin, encoded by Zfp36, is needed for CD8 T-cell production of IFN-γ in vivo. When activated in vitro, however, IFN-γ production by naive wild type and tristetraprolin-deficient CD8 T-cells is comparable. IL-27 is overproduced by tristetraprolin-deficient macrophages and increased systemically in tristetraprolin-deficient mice. Tristetraprolin suppresses IL-27 production by promoting p28 mRNA degradation. Importantly, deletion of IL-27 receptor WSX-1 in tristetraprolin-deficient mice (WSX-1/tristetraprolin double knockout) leads to a reduction in cytotoxic T lymphocyte numbers. Moreover, tumor growth is accelerated, not only in tristetraprolin-deficient mice after cytotoxic T lymphocyte depletion, but also in WSX-1/tristetraprolin double knockout mice, with substantial reduction in the number of tumor cytotoxic T lymphocytes. This study describes a regulatory pathway for IL-27 expression and cytotoxic T lymphocyte function mediated by tristetraprolin, contributing to regulation of antitumour immunity.IL-27 is one of a number of cytokines that can induce antitumour CD8 T cell responses. Here the authors show that TTP, encoded by Zfp36, degrades p28 to inhibit IL-27 production by macrophages and is thereby a negative regulator of the antitumour response.
Topics: Animals; Female; Gene Expression Regulation; Interferon-gamma; Interleukins; Macrophages; Mammary Neoplasms, Experimental; Mice, Inbred C57BL; Mice, Knockout; Receptors, Cytokine; Receptors, Interleukin; T-Lymphocytes, Cytotoxic; Tristetraprolin
PubMed: 29021521
DOI: 10.1038/s41467-017-00892-y