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International Journal of Molecular... Oct 2018Genetic loss or mutations in tumor suppressor genes promote tumorigenesis. The prospective tumor suppressor tristetraprolin (TTP) has been shown to negatively regulate... (Review)
Review
Genetic loss or mutations in tumor suppressor genes promote tumorigenesis. The prospective tumor suppressor tristetraprolin (TTP) has been shown to negatively regulate tumorigenesis through destabilizing the messenger RNAs of critical genes implicated in both tumor onset and tumor progression. Regulation of TTP has therefore emerged as an important issue in tumorigenesis. Similar to other tumor suppressors, TTP expression is frequently downregualted in various human cancers, and its low expression is correlated with poor prognosis. Additionally, disruption in the regulation of TTP by various mechanisms results in the inactivation of TTP protein or altered TTP expression. A recent study showing alleviation of Myc-driven lymphomagenesis by the forced expression of TTP has shed light on new therapeutic avenues for cancer prevention and treatment through the restoration of TTP expression. In this review, we summarize key oncogenes subjected to the TTP-mediated mRNA degradation, and discuss how dysregulation of TTP can contribute to tumorigenesis. In addition, the control mechanism underlying TTP expression at the posttranscriptional and posttranslational levels will be discussed.
Topics: Animals; Carcinogenesis; Disease Progression; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Humans; Neoplasms; RNA Stability; RNA, Messenger; Tristetraprolin
PubMed: 30380668
DOI: 10.3390/ijms19113384 -
Anti-cancer Agents in Medicinal... Nov 2017Cytokines are small secreted proteins serving as vital mediators that mediate the host immune responses. Transcription and post-transcription play a critical role in... (Review)
Review
Cytokines are small secreted proteins serving as vital mediators that mediate the host immune responses. Transcription and post-transcription play a critical role in cytokine expression through the regulation of message RNA (mRNA) cytoplasmic localization, translation initiation and decay. Researches have been conducted to reveal regulatory mechanisms of cytokines production in cells involved in cancer. AU-rich element (ARE) can regulate the degradation and translation of mRNA by connecting with specific ARE binding proteins. It is now clear that tristetraprolin (TTP), as the most common ARE binding protein, negatively regulates many aspects of the cytokines through binding to the AREs in the 3'-untranslated region (3'UTR) of mRNA. Furthermore, some certain cytokines have an impact on TTP expression and function. Therefore, the cross-regulation between cytokines and TTP has come into sight. The complicated regulatory networks between cytokines and TTP are closely related to tumorigenesis. In this review, we summarize specific regulatory mechanisms of cytokine mRNAs. We focus on how TTP negatively regulates inflammatory and oncogenic cytokines expression after combining with AREs, we also pay attention to some cytokines mediating the expression of TTP and their cross-talk in various cancers in detail.
Topics: Animals; Cytokines; Humans; Neoplasms; RNA, Messenger; Tristetraprolin
PubMed: 28356023
DOI: 10.2174/1871520617666170327155124 -
Molecular Genetics and Metabolism Jun 2021Tristetraprolin (TTP) is a nucleocytoplasmic 326 amino acid protein whose sequence is characterized by possessing two CCCH-type zinc finger domains. In the cytoplasm TTP... (Review)
Review
Tristetraprolin (TTP) is a nucleocytoplasmic 326 amino acid protein whose sequence is characterized by possessing two CCCH-type zinc finger domains. In the cytoplasm TTP function is to promote the degradation of mRNAs that contain adenylate/uridylate-rich elements (AREs). Mechanistically, TTP promotes the recruitment of poly(A)-specific deadenylases and exoribonucleases. By reducing the half-life of about 10% of all the transcripts in the cell TTP has been shown to participate in multiple cell processes that include regulation of gene expression, cell proliferation, metabolic homeostasis and control of inflammation and immune responses. However, beyond its role in mRNA decay, in the cell nucleus TTP acts as a transcriptional coregulator by interacting with chromatin modifying enzymes. TTP has been shown to repress the transactivation of NF-κB and estrogen receptor suggesting the possibility that it participates in the transcriptional regulation of hundreds of genes in human cells and its possible involvement in breast cancer progression. In this review, we discuss the cytoplasmic and nuclear functions of TTP and the effect of the dysregulation of its protein levels in the development of human diseases. We suggest that TTP be classified as a moonlighting tumor supressor protein that regulates gene expression through two different mechanims; the decay of ARE-mRNAs and a transcriptional coregulatory function.
Topics: Cell Proliferation; Cytosol; Gene Expression Regulation; Humans; Inflammation; RNA Stability; RNA, Messenger; Transcriptional Activation; Tristetraprolin; Zinc Fingers
PubMed: 33795191
DOI: 10.1016/j.ymgme.2021.03.015 -
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 -
Clinical implications of tristetraprolin (TTP) modulation in the treatment of inflammatory diseases.Pharmacology & Therapeutics Nov 2022Abnormal regulation of pro-inflammatory cytokine and chemokine mediators can contribute to the excess inflammation characteristic of many autoimmune diseases, such as... (Review)
Review
Abnormal regulation of pro-inflammatory cytokine and chemokine mediators can contribute to the excess inflammation characteristic of many autoimmune diseases, such as rheumatoid arthritis, psoriasis, Crohn's disease, type 1 diabetes, and many others. The tristetraprolin (TTP) family consists of a small group of related RNA-binding proteins that bind to preferred AU-rich binding sites within the 3'-untranslated regions of specific mRNAs to promote mRNA deadenylation and decay. TTP deficient mice develop a severe systemic inflammatory syndrome consisting of arthritis, myeloid hyperplasia, dermatitis, autoimmunity and cachexia, due at least in part to the excess accumulation of proinflammatory chemokine and cytokine mRNAs and their encoded proteins. To investigate the possibility that increased TTP expression or activity might have a beneficial effect on inflammatory diseases, at least two mouse models have been developed that provide proof of principle that increasing TTP activity can promote the decay of pro-inflammatory and other relevant transcripts, and decrease the severity of mouse models of inflammatory disease. Animal studies of this type are summarized here, and we briefly review the prospects for harnessing these insights for the development of TTP-based anti-inflammatory treatments in humans.
Topics: Humans; Mice; Animals; Tristetraprolin; RNA, Messenger; Inflammation; Cytokines; Autoimmune Diseases
PubMed: 35525391
DOI: 10.1016/j.pharmthera.2022.108198 -
Molecular Pharmacology Apr 2015Chronic inflammatory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), are clinically and socioeconomically important diseases globally.... (Review)
Review
Chronic inflammatory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), are clinically and socioeconomically important diseases globally. Currently the mainstay of anti-inflammatory therapy in respiratory diseases is corticosteroids. Although corticosteroids have proven clinical efficacy in asthma, many asthmatic inflammatory conditions (e.g., infection, exacerbation, and severe asthma) are not responsive to corticosteroids. Moreover, despite an understanding that COPD progression is driven by inflammation, we currently do not have effective anti-inflammatory strategies to combat this disease. Hence, alternative anti-inflammatory strategies are required. p38 mitogen-activated protein kinase (MAPK) has emerged as an important signaling molecule driving airway inflammation, and pharmacological inhibitors against p38 MAPK may provide potential therapies for chronic respiratory disease. In this review, we discuss some of the recent in vitro and in vivo studies targeting p38 MAPK, but suggest that p38 MAPK inhibitors may prove less effective than originally considered because they may block anti-inflammatory molecules along with proinflammatory responses. We propose that an alternative strategy may be to target an anti-inflammatory molecule farther downstream of p38 MAPK, i.e., tristetraprolin (TTP). TTP is an mRNA-destabilizing, RNA-binding protein that enhances the decay of mRNAs, including those encoding proteins implicated in chronic respiratory diseases. We suggest that understanding the molecular mechanism of TTP expression and its temporal regulation will guide future development of novel anti-inflammatory pharmacotherapeutic approaches to combat respiratory disease.
Topics: Adrenal Cortex Hormones; Animals; Anti-Inflammatory Agents; Humans; Inflammation; Pulmonary Disease, Chronic Obstructive; Respiratory System; Respiratory Tract Diseases; Tristetraprolin; p38 Mitogen-Activated Protein Kinases
PubMed: 25429052
DOI: 10.1124/mol.114.095984 -
Ageing Research Reviews Sep 2012Cancer and senescence are both complex transformative processes that dramatically alter many features of cell physiology and their interactions with surrounding tissues.... (Review)
Review
Cancer and senescence are both complex transformative processes that dramatically alter many features of cell physiology and their interactions with surrounding tissues. Developing the wide range of cellular features characteristic of these conditions requires profound alterations in global gene expression patterns, which can be achieved by suppressing, activating, or uncoupling cellular gene regulatory pathways. Many genes associated with the initiation and development of tumors are regulated at the level of mRNA decay, frequently through the activity of AU-rich mRNA-destabilizing elements (AREs) located in their 3'-untranslated regions. As such, cellular factors that recognize and control the decay of ARE-containing mRNAs can influence tumorigenic or senescent phenotypes mediated by products of these transcripts. In this review, we discuss evidence showing how suppressed expression and/or activity of the ARE-binding protein tristetraprolin (TTP) can contribute to these processes. Next, we outline current findings linking TTP suppression to exacerbation of individual tumorigenic phenotypes, and the roles of specific TTP substrate mRNAs in mediating these effects. Finally, we survey potential mechanisms that cells may employ to suppress TTP expression in cancer, and propose potential diagnostic and therapeutic strategies that may exploit the relationship between TTP expression and tumor progression or senescence.
Topics: Aging; Animals; Cell Transformation, Neoplastic; Cellular Senescence; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; RNA Processing, Post-Transcriptional; RNA Stability; Tristetraprolin
PubMed: 22387927
DOI: 10.1016/j.arr.2012.02.005 -
Cellular Signalling Feb 2021Tristetraprolin (TTP) is a destabilizing mRNA binding protein known to regulate gene expression of a wide variety of targets, including those that control inflammation.... (Review)
Review
Tristetraprolin (TTP) is a destabilizing mRNA binding protein known to regulate gene expression of a wide variety of targets, including those that control inflammation. TTP expression, regulation and function is controlled by phosphorylation. While the importance of key serine (S) sites (S and S in mice and S in humans) has been recognized, other sites on the hyperphosphorylated TTP protein have more recently emerged as playing an important role in regulating cellular signalling and downstream functions of TTP. In order to propel investigation of TTP and fully exploit its potential as a drug target in inflammatory disease, this review will catalogue TTP phosphorylation sites in both the murine and human TTP protein, the known and unknown roles and functions of these sites, the kinases and phosphatases that act upon TTP and overview methodological approaches to increase our knowledge of this important protein regulated by phosphorylation.
Topics: Animals; Humans; Mice; Phosphorylation; Protein Domains; Tristetraprolin
PubMed: 33276085
DOI: 10.1016/j.cellsig.2020.109868 -
Frontiers in Immunology 2022Aging results in enhanced myelopoiesis, which is associated with an increased prevalence of myeloid leukemias and the production of myeloid-derived suppressor cells...
Aging results in enhanced myelopoiesis, which is associated with an increased prevalence of myeloid leukemias and the production of myeloid-derived suppressor cells (MDSCs). Tristetraprolin (TTP) is an RNA binding protein that regulates immune-related cytokines and chemokines by destabilizing target mRNAs. As TTP expression is known to decrease with age in myeloid cells, we used TTP-deficient (TTPKO) mice to model aged mice to study TTP regulation in age-related myelopoiesis. Both TTPKO and myeloid-specific TTPKO (cTTPKO) mice had significant increases in both MDSC subpopulations M-MDSCs (CD11bLy6CLy6G) and PMN-MDSCs (CD11bLy6CLy6G), as well as macrophages (CD11bF4/80) in the spleen and mesenteric lymph nodes; however, no quantitative changes in MDSCs were observed in the bone marrow. In contrast, gain-of-function TTP knock-in (TTPKI) mice had no change in MDSCs compared with control mice. Within the bone marrow, total granulocyte-monocyte progenitors (GMPs) and monocyte progenitors (MPs), direct antecedents of M-MDSCs, were significantly increased in both cTTPKO and TTPKO mice, but granulocyte progenitors (GPs) were significantly increased only in TTPKO mice. Transcriptomic analysis of the bone marrow myeloid cell populations revealed that the expression of CC chemokine receptor 2 (CCR2), which plays a key role in monocyte mobilization to inflammatory sites, was dramatically increased in both cTTPKO and TTPKO mice. Concurrently, the concentration of CC chemokine ligand 2 (CCL2), a major ligand of CCR2, was high in the serum of cTTPKO and TTPKO mice, suggesting that TTP impacts the mobilization of M-MDSCs from the bone marrow to inflammatory sites during aging regulation of the CCR2-CCL2 axis. Collectively, these studies demonstrate a previously unrecognized role for TTP in regulating age-associated myelopoiesis through the expansion of specific myeloid progenitors and M-MDSCs and their recruitment to sites of injury, inflammation, or other pathologic perturbations.
Topics: Mice; Animals; Myeloid-Derived Suppressor Cells; Receptors, CCR2; Tristetraprolin; Ligands; Chemokines; Cytokines; Chemokines, CC
PubMed: 36263047
DOI: 10.3389/fimmu.2022.1002163 -
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