Tristetraprolin: Roles in cancer and senescence

Ross, Christina R.; Brennan-Laun, Sarah E.; Wilson, Gerald M.

doi:10.1016/j.arr.2012.02.005

Cited by 56 publications

(57 citation statements)

References 153 publications

(194 reference statements)

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“…TTP is also induced by mitogens and functions to attenuate the expression of a subset of mitogeninduced ARE-containing transcripts (64,65). Our data suggest that RNase L functions in association with TTP to degrade SRF mRNA providing a mechanism to limit SRF-induced transcription.…”

Section: Rnase L and Ttp Function To Down-regulate The Expression Of mentioning

confidence: 78%

“…However, the functional significance of this regulation and the biologic contexts in which it occurs are not known. The major biologic functions attributed to TTP occur following the induction of its expression or activity by diverse stimuli, including mitogens (7,64,65). In light of the overlapping roles for RNase L and TTP in antiproliferative and tumor suppressor activities, we examined the regulation of TTP by RNase L in the context of mitogen stimulation as a potential mechanism by which the proliferative response is attenuated.…”

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confidence: 99%

“…Established TTP targets include transcripts that encode mediators of cell proliferation such as c-Myc (56), hypoxia-inducible factor 1, ␣ (HIF1-␣) (57), cyclooxygenase 2 (Cox-2) (58), and proviral integration site 1 (59). Increased TTP-mediated turnover of these transcripts results in proliferation-inhibitory activities, including cell cycle arrest (60), senescence (61), apoptosis (5)(6)(7)62), and tumor suppression in vivo (5,63,64). A subset of TTP targets exhibit RNase L-dependent regulation supporting a potential role for TTP in targeting RNase L substrate cleavage (45).…”

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confidence: 99%

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RNase L Attenuates Mitogen-stimulated Gene Expression via Transcriptional and Post-transcriptional Mechanisms to Limit the Proliferative Response

Brennan-Laun

Ezelle

et al. 2014

Journal of Biological Chemistry

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Background: Serum-response factor (SRF) induces mRNAs that promote cell proliferation, whereas RNase L and tristetraprolin (TTP) degrade specific mRNAs to inhibit proliferation. Results: RNase L and TTP interact and down-regulate SRF to attenuate mitogen-induced gene expression. Conclusion: RNase L and TTP are components of a regulatory network that limits the proliferative response to mitogens. Significance: The RNase L/TTP axis represents a target to inhibit cancer cell proliferation.

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Section: Rnase L and Ttp Function To Down-regulate The Expression Of mentioning

confidence: 78%

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confidence: 99%

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confidence: 99%

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RNase L Attenuates Mitogen-stimulated Gene Expression via Transcriptional and Post-transcriptional Mechanisms to Limit the Proliferative Response

Brennan-Laun

Ezelle

et al. 2014

Journal of Biological Chemistry

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“…Tristetraprolin can destabilize TNFα and vascular endothelial growth factor mRNAs. 131 Tristetraprolin induces senescence in human papillomavirus-transformed cervical cancer cells by targeting E6-AP ubiquitin ligase. 132 However, it remains unknown whether tristetraprolin is involved in vascular aging.…”

Section: Degradation Of Nucleic Acids and Agingmentioning

confidence: 99%

Macromolecular Degradation Systems and Cardiovascular Aging

Nakayama

Nishida

Otsu³

2016

Circulation Research

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7Cardiovascular aging or age-associated cardiovascular diseases include atherosclerosis, coronary artery disease, hypertension, heart failure, and atrial fibrillation. In addition, aged hearts are characterized by decreased contractility, impaired diastolic function, and atrium dilatation, indicating that both the functional and the morphological alterations that result in these diseases of the heart occur during the aging process. Abstract: Aging-related cardiovascular diseases are a rapidly increasing problem worldwide. Cardiac aging demonstrates progressive decline of diastolic dysfunction of ventricle and increase in ventricular and arterial stiffness accompanied by increased fibrosis stimulated by angiotensin II and proinflammatory cytokines. Reactive oxygen species and multiple signaling pathways on cellular senescence play major roles in the process. Aging is also associated with an alteration in steady state of macromolecular dynamics including a dysfunction of protein synthesis and degradation. Currently, impaired macromolecular degradation is considered to be closely related to enhanced inflammation and be involved in the process and mechanism of cardiac aging. Herein, we review the role and mechanisms of the degradation system of intracellular macromolecules in the process and pathophysiology of cardiovascular aging.

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“…This was confirmed by the observations that treatment with anti-TNF antibodies or interbreeding the TTP KO mice with mice lacking both TNF receptors prevented the development of the inflammatory phenotype (7,8). Subsequent studies on bone marrow-derived macrophages from these animals demonstrated that the TNF mRNA is a direct target of TTP and that the binding of TTP to binding sites in the 3=UTR of TNF mRNA could promote its decay (9, 10).Since the early demonstration of TNF mRNA as an important physiological target of TTP, many other mRNAs have been identified as real or potential TTP targets (11)(12)(13)(14). Many of these putative target transcripts have been identified and studied in primary cells derived from the TTP KO mice or in cultured cells in which TTP was knocked down by other techniques.…”

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confidence: 99%

Effects of Combined Tristetraprolin/Tumor Necrosis Factor Receptor Deficiency on the Splenic Transcriptome

Patial¹,

Stumpo²,

Young

et al. 2016

Molecular and Cellular Biology

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e Tristetraprolin (TTP) acts by binding to AU-rich elements in certain mRNAs, such as tumor necrosis factor (TNF) mRNA, and increasing their decay rates. TTP knockout mice exhibit a profound inflammatory syndrome that is largely due to increased TNF levels. Although TTP's effects on gene expression have been well studied in cultured cells, little is known about its functions in intact tissues. We performed deep RNA sequencing on spleens from TTP knockout mice that were also deficient in both TNF receptors ("triple knockout" mice) to remove the secondary effects of excess TNF activity. To help identify posttranscriptionally regulated transcripts, we also compared changes in mature mRNA levels to levels of transiently expressed pre-mRNA. In the triple knockout spleens, levels of 3,014 transcripts were significantly affected by 1.5-fold or more, but only a small fraction exhibited differential mRNA/pre-mRNA changes suggestive of increased mRNA stability. Transferrin receptor mRNA, which contains two highly conserved potential TTP binding sites, was significantly upregulated relative to its pre-mRNA. This was reflected in increased transferrin receptor expression and increased splenic iron/hemosiderin deposition. Our results suggest that TTP deficiency has profound effects on the splenic transcriptome, even in the absence of secondary increases in TNF activity. Members of the tristetraprolin (TTP) family of CCCH tandem zinc finger proteins can bind to AU-rich elements (AREs) in the 3= untranslated regions (3=UTR) of certain mRNAs and promote their turnover. The ideal binding site appears to be UUAU UUAUU, although variations of this sequence can be tolerated with relatively minor changes in affinity (1-5). TTP and its other family members can bind with high affinity to these AREs and then promote the removal of the poly(A) tail and the ultimate destruction of the transcript (6).The protein members of the TTP family in mice are as follows: TTP itself, encoded by Zfp36; ZFP36L1, also known as BRF1, ERF1, and CMG1, encoded by Zfp36l1; ZFP36L2, also known as BRF2 and ERF2, encoded by Zfp36l2; and ZFP36L3, encoded by Zfp36l3. The identification of TTP, the best-studied member of this family, as an mRNA-destabilizing protein was first recognized by analyzing the phenotype of TTP knockout (KO) mice, which exhibited a severe systemic inflammatory phenotype with polyarticular erosive arthritis, weight loss, dermatitis, autoimmunity, and myeloid hyperplasia (7). The nature of this syndrome suggested excess tumor necrosis factor alpha (TNF) as a causative agent. This was confirmed by the observations that treatment with anti-TNF antibodies or interbreeding the TTP KO mice with mice lacking both TNF receptors prevented the development of the inflammatory phenotype (7,8). Subsequent studies on bone marrow-derived macrophages from these animals demonstrated that the TNF mRNA is a direct target of TTP and that the binding of TTP to binding sites in the 3=UTR of TNF mRNA could promote its decay (9, 10).Since the early demonstration...

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Tristetraprolin: Roles in cancer and senescence

Cited by 56 publications

References 153 publications

RNase L Attenuates Mitogen-stimulated Gene Expression via Transcriptional and Post-transcriptional Mechanisms to Limit the Proliferative Response

RNase L Attenuates Mitogen-stimulated Gene Expression via Transcriptional and Post-transcriptional Mechanisms to Limit the Proliferative Response

Macromolecular Degradation Systems and Cardiovascular Aging

Effects of Combined Tristetraprolin/Tumor Necrosis Factor Receptor Deficiency on the Splenic Transcriptome

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