Multiple tristetraprolin sequence domains required to induce apoptosis and modulate responses to TNFα through distinct pathways

Johnson, Barbra A.; Blackwell, T. Keith

doi:10.1038/sj.onc.1205526

Cited by 54 publications

(58 citation statements)

References 56 publications

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“…Consistent with the model that TTP/TIS11 proteins influence growth, survival, or apoptotic signals, we have determined that their constitutive expression at modest levels induces apoptosis through the mitochondrial pathway (31). We have also shown that TTP has diverged functionally from the other two TTP/TIS11 proteins, in that TTP alone dramatically sensitizes cells to the apoptotic stimulus of TNF␣ (31,32). This last finding suggests that TTP could contribute to the cellular decision between activation or apoptosis in response to TNF␣.…”

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confidence: 69%

“…Although the isolated TTP zinc finger region can mediate its effects on TNF␣ mRNA stability in transfection assays (16), we have observed that the TTP zinc finger region is incapable of inducing apoptosis or of sensitizing cells to TNF␣-induced apoptosis (32). Together with the zinc fingers, the TTP N-and C-terminal regions each contribute to induction of apoptosis, and the N-terminal region is specifically required to sensitize cells to TNF␣ (32).…”

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confidence: 97%

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Cytoplasmic Localization of Tristetraprolin Involves 14-3-3-dependent and -independent Mechanisms

Johnson¹,

Stehn²,

Yaffe³

et al. 2002

Journal of Biological Chemistry

118

125

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The immediate early gene tristetraprolin (TTP) is induced transiently in many cell types by numerous extracellular stimuli. TTP encodes a zinc finger protein that can bind and destabilize mRNAs that encode tumor necrosis factor-alpha (TNF␣) and other cytokines. We hypothesize that TTP also has a broader role in growth factor-responsive pathways. In support of this model, we have previously determined that TTP induces apoptosis through the mitochondrial pathway, analogously to certain oncogenes and other immediate-early genes, and that TTP sensitizes cells to the pro-apoptotic signals of TNF␣. In this study, we show that TTP and the related proteins TIS11b and TIS11d bind specifically to 14-3-3 proteins and that individual 14-3-3 isoforms preferentially bind to different phosphorylated TTP species. 14-3-3 binding does not appear to inhibit or promote induction of apoptosis by TTP but is one of multiple mechanisms that localize TTP to the cytoplasm. Our results provide the first example of 14-3-3 interacting functionally with an RNA binding protein and binding in vivo to a Type II 14-3-3 binding site. They also suggest that 14-3-3 binding is part of a complex network of stimuli and interactions that regulate TTP function.The immediate-early protein tristetraprolin (TTP 1 ; also Nup475 and TIS11) is expressed transiently during responses to many extracellular stimuli, including TNF␣ (1). TTP and the related proteins TIS11b and TIS11d (TTP/TIS11 proteins) consist of two conserved Cys-X 8 -Cys-X 5 -Cys-X 3 -His (CCCH) zinc fingers, along with similarly sized but divergent N-and Cterminal regions. Several lines of evidence indicate that TTP binds and destabilizes cytokine mRNAs, through binding to an AU-rich element (ARE) located within their 3Ј-untranslated regions. This ARE is targeted by conserved signaling pathways, which regulate the localization, stability, and translation of these mRNAs (2-9). TTPϪ/Ϫ mice develop a widespread inflammatory syndrome that is mediated largely by TNF␣ and is associated with elevated levels and half-life of the TNF␣ mRNA (10 -13). A protein complex that contains TTP binds to the TNF␣ ARE (14) and in transfection assays each TTP/TIS11 protein can bind and destabilize cytokine mRNAs that have related AREs (1,12,(15)(16)(17). These findings suggest that TTP limits expression of TNF␣ and other cytokines through a feedback mechanism, by destabilizing their mRNAs, and that this is a shared function of TTP/TIS11 proteins. Some other CCCH zinc finger proteins appear to regulate translation of their target genes (18 -21), suggesting that many members of this protein family may regulate specific genes post-transcriptionally.It appears likely that TTP has additional functions and may play a broader role during responses to extracellular stimuli. TTP expression is induced rapidly and directly in numerous cultured cell types, by a wide variety of growth factors and mitogens (22)(23)(24). In mice, TTP is expressed in developing oocytes and regenerating small intestine and liver, in addition to hem...

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confidence: 69%

mentioning

confidence: 97%

Cytoplasmic Localization of Tristetraprolin Involves 14-3-3-dependent and -independent Mechanisms

Johnson¹,

Stehn²,

Yaffe³

et al. 2002

Journal of Biological Chemistry

118

125

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“…TTP binds to AREs from RNAs coding for immediate-early genes such as c-fos, interleukin-3, and TNF-␣ (39,44,46,47) and confers instability to these messages. TTP also has a physiological role in the induction of apoptosis (48). We report that TTP is expressed in HCA-7 cells, that its transcription is up-regulated with cell confluence, and that levels of its RNA vary inversely with those of the full-length COX-2 mRNA.…”

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confidence: 93%

Tristetraprolin Binds to the 3′-Untranslated Region of Cyclooxygenase-2 mRNA

Sawaoka¹,

Dixon²,

Oates³

et al. 2003

Journal of Biological Chemistry

130

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In human colorectal adenocarcinoma cell lines, we found two major transcripts of cyclooxygenase-2, the full-length mRNA and a short polyadenylation variant (2577 kb) lacking the distal segment of the 3 -untranslated region. Tristetraprolin, an mRNA-binding protein that promotes message instability, was shown to bind the cyclooxygenase-2 mRNA in the region of the 3 -untranslated region between nucleotides 3125 and 3432 and to reduce levels of the full-length mRNA. During cell growth and confluence, the expression of tristetraprolin mRNA was inversely correlated with that of the fulllength cyclooxygenase-2 transcript, and transfection of tristetraprolin into HCA-7 cells reduced the level of fulllength cyclooxygenase-2 mRNA. However, the truncated transcript escaped tristetraprolin binding and downregulation.

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“…Tritetraprolin (-3.0) is a TNF-␣-induced product that blocks TNF-␣ production by facilitating degradation of TNF-␣ mRNA (26). PKC interacting cousin of thioredoxin 2 (Ϫ2.5) is an inhibitor of two factors important for T cell activation: NF-B and AP1 (27).…”

Section: Molecular Characterization Of the Host Response At The Fs͞z mentioning

confidence: 99%

The impact of parietal cells onHelicobacter pyloritropism and host pathology: An analysis using gnotobiotic normal and transgenic mice

Syder

Guruge

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Helicobacter pylori infection of the human stomach is common and typically benign, although a subset of hosts develops severe pathology. Infection occurs in an organ with distinct microenvironments characterized by pronounced differences in the composition of acid-producing parietal cells. In this study, we examine determinants of bacterial tropism to various gastric niches by using germ-free normal and transgenic mice with an engineered parietal cell ablation. Mice were colonized for 8 weeks with a clinical isolate (Hp1) that expresses adhesins recognized by epithelial NeuAc␣2,3Gal␤1,4 glycan receptors. In normal mice, Hp1 has tropism for a parietal cell-deficient niche where sialylated glycans are expressed by a narrow band of pit cells positioned at the boundary between the squamous epithelium (forestomach) and the proximal glandular epithelium. Lymphoid aggregates that develop in this niche, but not elsewhere in the stomach, were analyzed by GeneChip and quantitative RT-PCR studies of laser capture microdissected mucosa and yielded a series of biomarkers indicative of immune cell activation and maturation. Genetic ablation of parietal cells produced a new source of NeuAc␣2,3Gal␤1,4 glycans in amplified gastric epithelial lineage progenitors, with accompanying expansion of Hp1 within the glandular epithelium. Lymphoid aggregates that develop in this formerly acid-protected epithelium have molecular features similar to those observed at the forestomach͞glandular junction. These findings demonstrate the important roles played by parietal cells and glycan receptors in determining the positioning of H. pylori within the gastric ecosystem, and emphasize the need to consider the evolution of pathology within a given host in a niche-specific context. gastric acid ͉ adhesin receptors ͉ immune response ͉ germ-free animals A t least half of all humans harbor Helicobacter pylori in their stomachs. This microaerophilic bacterium is usually acquired in childhood and remains in the stomach of its host for decades (1). In most cases, the host-microbial relationship is benign, marked only by mild mucosal inflammation. However, in a subset of individuals, this relationship evolves to produce gastric or duodenal ulcers, adenocarcinoma, or mucosal lymphoma (2).Lee and coworkers (3) have emphasized that severe pathology more often develops in regions of the gastric epithelium where there is a marked transition in the census of acid-producing parietal cells. They and others proposed that local environmental pH gradients at these transitions provide the organism with an opportunity to sample and occupy niches where growth conditions are optimal (3, 4). Once the organism becomes entrenched, pH and other niche-associated factors (e.g., redox state, nutrient availability) then presumably shape the nature of the host-microbial interaction (5).These speculations emphasize the importance of viewing the nature of the host-microbial cross-talk, the genetic microevolution of this bacterium (6, 7), and the structure of the pathogenic cascad...

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Multiple tristetraprolin sequence domains required to induce apoptosis and modulate responses to TNFα through distinct pathways

Cited by 54 publications

References 56 publications

Cytoplasmic Localization of Tristetraprolin Involves 14-3-3-dependent and -independent Mechanisms

Cytoplasmic Localization of Tristetraprolin Involves 14-3-3-dependent and -independent Mechanisms

Tristetraprolin Binds to the 3′-Untranslated Region of Cyclooxygenase-2 mRNA

The impact of parietal cells onHelicobacter pyloritropism and host pathology: An analysis using gnotobiotic normal and transgenic mice

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