Similar but distinct effects of the tristetraprolin/TIS11 immediate-early proteins on cell survival

Johnson, Barbra A.; Geha, Mayya; Blackwell, T. Keith

doi:10.1038/sj.onc.1203474

Cited by 77 publications

(87 citation statements)

References 55 publications

(72 reference statements)

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“…Like some other immediate early proteins, in certain contexts TTP is also expressed during induction of apoptosis (27)(28)(29)(30). 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).…”

supporting

confidence: 50%

“…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␣.…”

mentioning

confidence: 70%

“…Cell death was assayed by co-transfection of a ␤-galactosidase reporter and examination of cell morphology after X-gal staining 24 h later (31). Under a variety of conditions, numbers of apoptotic cells identified by this method were reproducibly comparable to those detected by scoring Hoechst-stained pyknotic nuclei (not shown) (31). For serum-dependent relocalization assays, cells were washed twice in Dulbecco's modified Eagle's medium (DMEM) prior to transfection, and DMEM without serum was added 3 h later.…”

Section: Methodsmentioning

confidence: 99%

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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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supporting

confidence: 50%

mentioning

confidence: 70%

Section: Methodsmentioning

confidence: 99%

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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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“…Since a series of regulators relevant for oncogenic growth including cyclins, growth factors and proto-oncogenes contain AREs with an UUAUUUAUU motif (Chen and Shyu, 1995), it is conceivable that TTP in fact has a broader spectrum of target mRNAs in the tumor cells. Such targets may also include antiapoptotic genes, as continuous expression of TTP was observed to induce apoptosis in various cell lines (Johnson et al, 2000). Although we formally cannot exclude the possibility of .…”

Section: Discussionmentioning

confidence: 99%

A novel mechanism of tumor suppression by destabilizing AU-rich growth factor mRNA

et al. 2003

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The occurrence of pathologically stable mRNAs of protooncogenes, growth factors and cyclins has been proposed to contribute to experimental and human oncogenesis. In normal resting cells, mRNAs containing an AU-rich element (ARE) in their 3 0 untranslated region are subjected to rapid degradation. Tristetraprolin (TTP) is an RNA-binding zinc-finger protein that promotes decay of ARE-containing mRNAs. Here we report that TTP acts as a potent tumor suppressor in a v-H-ras-dependent mast cell tumor model, where tumors express abnormally stable interleukin-3 (IL-3) mRNA as part of an oncogenic autocrine loop. Premalignant v-H-ras cells were transfected with TTP and injected into syngeneic mice. TTP expression delayed tumor progression by 4 weeks, and late appearing tumors escaped suppression by loss of TTP. When transfected into a fully established tumor line, TTP reduced cloning efficiency in vitro and growth of the inoculated cells in vivo. Transgenic TTP interfered with the autocrine loop by enhancing the degradation of IL-3 mRNA with concomitant reduction of IL-3 secretion. Our data establish the ARE as an antioncogenic target in a model situation, underline the importance of mRNA stabilization in oncogenesis and show for the first time that tumor suppression can be achieved by interfering with mRNA turnover.

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“…7,8 Several publications demonstrate that TTP family proteins are phosphorylated 9 and are possible targets along the p38 MAPK pathway. 10,11 At the biological level, TTP family members have been described as involved in cell differentiation and apoptosis, 12,13 in the regulation of the cell response to growth factors and in the development of cancer. In particular, it has been demonstrated that TTP proteins target and destabilize mRNAs encoding growth factors' signaling transducers, particularly downstream of EGF 14 and IGF-I receptors.…”

Section: Introductionmentioning

confidence: 99%

ZFP36 expression impairs glioblastoma cell lines viability and invasiveness by targeting multiple signal transduction pathways

et al. 2012

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Similar but distinct effects of the tristetraprolin/TIS11 immediate-early proteins on cell survival

Cited by 77 publications

References 55 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

A novel mechanism of tumor suppression by destabilizing AU-rich growth factor mRNA

ZFP36 expression impairs glioblastoma cell lines viability and invasiveness by targeting multiple signal transduction pathways

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