Inhibition of ATF4 Transcriptional Activity by FIAT/γ‐Taxilin Modulates Bone Mass Accrual

Yu, Vionnie W.C.; Gauthier, Claude; St‐Arnaud, René

doi:10.1196/annals.1346.027

Cited by 25 publications

(38 citation statements)

References 38 publications

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“…However, after we had reported the interaction of the taxilin family with α-and βNACs, Rene St-Arnaud and colleague have identified a protein identical to γ-taxilin in a yeast two-hybrid screen for proteins interacting with αNAC and named it factor inhibiting activating transcription factor 4 (ATF4)-mediated transcription (FIAT) (Yu et al, 2005). They have found that in calvarial osteoblasts from primary cultures, γ-taxilin/FIAT localizes to the nucleus, interacts with ATF4, and blocks ATF4-mediated transcription of the osteocalcin gene (Yu et al, 2005(Yu et al, , 2006. Therefore, it is possible that under certain conditions, α-taxilin is also translocated to the nucleus and subsequently modulates gene expression.…”

Section: Discussionmentioning

confidence: 99%

Interaction of α-taxilin Localized on Intracellular Components with the Microtubule Cytoskeleton

Horii

Nogami

Kawano

et al. 2012

Cell Struct. Funct.

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ABSTRACT. Intracellular vesicle traffic plays an essential role in the establishment and maintenance of organelle identity and biosynthetic transport. We have identified α-taxilin as a binding partner of the syntaxin family, which is involved in intracellular vesicle traffic. Recently, we have found that α-taxilin is over-expressed in malignant tissues including hepatocellular carcinoma and renal cell carcinoma. However, a precise role of α-taxilin in intracellular vesicle traffic and carcinogenesis remains unclear. Then, we first investigated here the intracellular distribution of α-taxilin in Hela cells. Immunofluorescence studies showed that α-taxilin distributes throughout the cytoplasm and exhibits a tubulo-vesicular pattern. Biochemical studies showed that α-taxilin is abundantly localized on intracellular components as a peripheral membrane protein. Moreover, we found that α-taxilin distributes in microtubule-dependent and syntaxin-independent manners, that α-taxilin directly binds to polymerized tubulin in vitro, and that N-ethylmaleimide but not brefeldin A affects the intracellular distribution of α-taxilin. These results indicate that α-taxilin is localized on intracellular components in a syntaxin-independent manner and that the α-taxilin-containing intracellular components are associated with the microtubule cytoskeleton and suggest that α-taxilin functions as a linker protein between the α-taxilin-containing intracellular components and the microtubule cytoskeleton.

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Section: Discussionmentioning

confidence: 99%

Interaction of α-taxilin Localized on Intracellular Components with the Microtubule Cytoskeleton

Horii

Nogami

Kawano

et al. 2012

Cell Struct. Funct.

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“…Recombinant FIAT protein dosedependently inhibited the binding of ATF4 to its response element [Yu et al, 2005]. In transient transfection assays in various cell types with heterologous or natural target reporters, co-expression of FIAT with ATF4 significantly inhibited ATF4-mediated transcription, even in the presence of RSK2 [Yu et al, 2005[Yu et al, , 2006a. Taken together, these results show that FIAT heterodimerizes with nuclear ATF4 to prevent its binding to DNA and repress its transcriptional activity.…”

mentioning

confidence: 58%

“…Detection of FIAT in the cytosol is in accord with the identification of FIAT as a protein that also interacts with the cytoplasmic syntaxin family members [Nogami et al, 2004]. FIAT was also shown to contact the transcriptional coactivator aNAC [Yoshida et al, 2005;Yu et al, 2006b], a protein that shuffles between the cytoplasm and the nucleus [Quelo et al, 2004a[Quelo et al, ,b, 2005. The decrease in FIAT protein levels observed in differentiating osteoblasts in culture coincided with increased binding of ATF4 to the Osteocalcin gene promoter, and with increased Osteocalcin transcription [Yu et al, 2009a].…”

mentioning

confidence: 72%

FIAT control of osteoblast activity

St‐Arnaud¹,

Mandic²

2009

J of Cellular Biochemistry

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The basic domain-leucine zipper transcription factor activating transcription factor 4 (ATF4) regulates most functions of the osteoblast. It is therefore not surprising that its activity should be regulated through several mechanisms. Factor inhibiting ATF4-mediated transcription (FIAT) is a leucine zipper nuclear molecule lacking a basic domain for DNA binding that interacts with ATF4 to repress its transcriptional activity. FIAT expression was monitored in parallel with ATF4 during osteoblastogenesis. The mechanism of ATF4 repression by FIAT was investigated through structure-function analysis. The physiological significance of FIAT expression in osteoblasts was studied through silencing FIAT in osteoblasts by RNA interference, as well as through characterization of two genetic mouse models: FIAT transgenic mice which overexpress FIAT in osteoblasts, and FIAT knockout mice. Studies to date show that FIAT and ATF4 are co-expressed in osteoblasts, and that FIAT inhibition of matrix mineralization requires dimerization with ATF4 through the second leucine zipper. Furthermore, transgenic mice overexpressing FIAT exhibit osteopenia. The phenotype of FIAT knockout mice is still under evaluation but the salient aspects are discussed here. Taken together, the results accumulated to date support the hypothesis that FIAT is a transcriptional repressor that modulates osteoblast function.

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“…Six differential proteins were identified by LC-MS/MS coupled to bioinformatics pattern discovery to predict treatment outcome, including five proteins having higher expression and the other one lower expression in patients with resistant tumor. Some of the identified proteins with differential expression are structural proteins (TMC5B and GFAP), and others are regulatory proteins of cell apoptosis (POTE E) and signal transcription (TXLNG) [12][13][14][15]. We do believe that informative molecules originating from tumor cells or their microenvironment may indeed be present in biological fluids and that their identification may lead to the discovery of potential new biomarkers.…”

Section: Discussionmentioning

confidence: 97%

Serum biomarkers analyzed by LC-MS/MS as predictors for short outcome of non-small cell lung cancer patients treated with chemoradiotherapy

Huang¹,

Ding²,

Li³

et al. 2012

neo

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Purpose: To find potential serum biomakers that can predict clinical outcome upon treatment in non-small cell lung cancer (NSCLC) by analyzing differential proteins in serum with different sensitivity of chemoradiotherapy (CRT).Materials and Methods: Sera were collected from 37 NSCLC patients before they were treated with concurrent cisplatinbased CRT. According to the outcome of CRT, the patients were divided into sensitive group and resistant one. The proteins in sera were separated by two-dimensional gel electrophoresis after the high abundance proteins were removed from sera. The significantly differentially expressed proteins between two groups were analyzed by liquid chromatography and tendem mass spectrometry (LC-MS/MS). Then, an additional 50 serum samples were used for ELISA analysis to validate the identified proteins that we got in the experiment.Results: Proteins in sera of each group were successfully separated on 2D gels. There were significant discrepancies in serum protein expression between NSCLC patients with different CRT sensitivity. Among eight differently expressed proteins, six proteins were successfully identified with five of which higher expressed and one lower expressed in resistant group. The increased Alpha-1-antitrypsin (α1-AT) level in resistant group comparing to sensitive one were validated by ELISA analysis (p<0.05).Conclusions: Proteomic approach may serve as a useful method in detecting the potential biomarkers for predicting the outcome of treatment in NSCLC patients. NSCLC patients with high α1-AT level in serum before CRT may have a worse treatment outcome.

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Inhibition of ATF4 Transcriptional Activity by FIAT/γ‐Taxilin Modulates Bone Mass Accrual

Cited by 25 publications

References 38 publications

Interaction of α-taxilin Localized on Intracellular Components with the Microtubule Cytoskeleton

Interaction of α-taxilin Localized on Intracellular Components with the Microtubule Cytoskeleton

FIAT control of osteoblast activity

Serum biomarkers analyzed by LC-MS/MS as predictors for short outcome of non-small cell lung cancer patients treated with chemoradiotherapy

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