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1.
J Cell Sci ; 123(Pt 20): 3558-65, 2010 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-20930144

RESUMO

The activating transcription factor 3 (ATF3) gene is induced by a variety of signals, including many of those encountered by cancer cells. We present evidence that ATF3 is induced by TGFß in the MCF10CA1a breast cancer cells and plays an integral role for TGFß to upregulate its target genes snail, slug and twist, and to enhance cell motility. Furthermore, ATF3 upregulates the expression of the TGFb gene itself, forming a positive-feedback loop for TGFß signaling. Functionally, ectopic expression of ATF3 leads to morphological changes and alterations of markers consistent with epithelial-to-mesenchymal transition (EMT). It also leads to features associated with breast-cancer-initiating cells: increased CD24(low)-CD44(high) population of cells, mammosphere formation and tumorigenesis. Conversely, knockdown of ATF3 reduces EMT, CD24(low)-CD44(high) cells and mammosphere formation. Importantly, knocking down twist, a downstream target, reduces the ability of ATF3 to enhance mammosphere formation, indicating the functional significance of twist in ATF3 action. To our knowledge, this is the first report demonstrating the ability of ATF3 to enhance breast cancer-initiating cell features and to feedback on TGFß. Because ATF3 is an adaptive-response gene and is induced by various stromal signals, these findings have significant implications for how the tumor microenvironment might affect cancer development.


Assuntos
Fator 3 Ativador da Transcrição/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Células-Tronco Neoplásicas/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Fator 3 Ativador da Transcrição/genética , Neoplasias da Mama/genética , Antígeno CD24/metabolismo , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Transição Epitelial-Mesenquimal/genética , Transição Epitelial-Mesenquimal/fisiologia , Feminino , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Receptores de Hialuronatos/metabolismo , Immunoblotting , Imunoprecipitação , Células-Tronco Neoplásicas/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa
2.
Gene Expr ; 15(1): 1-11, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-21061913

RESUMO

Activating transcription factor 3 (ATF3) gene encodes a member of the ATF family of transcription factors and is induced by various stress signals. All members of this family share the basic region-leucine zipper (bZip) DNA binding motif and bind to the consensus sequence TGACGTCA in vitro. Previous reviews and an Internet source have covered the following topics: the nomenclature of ATF proteins, the history of their discovery, the potential interplays between ATFs and other bZip proteins, ATF3-interacting proteins, ATF3 target genes, and the emerging roles of ATF3 in cancer and immunity (see footnote 1). In this review, we present evidence and clues that prompted us to put forth the idea that ATF3 functions as a "hub" of the cellular adaptive-response network. We will then focus on the roles of ATF3 in modulating inflammatory response. Inflammation is increasingly recognized to play an important role for the development of many diseases. Putting this in the context of the hub idea, we propose that modulation of inflammation by ATF3 is a unifying theme for the potential involvement of ATF3 in various diseases.


Assuntos
Fator 3 Ativador da Transcrição/metabolismo , Adaptação Fisiológica , Inflamação/etiologia , Inflamação/metabolismo , Transdução de Sinais , Fator 3 Ativador da Transcrição/química , Fator 3 Ativador da Transcrição/genética , Sequência de Aminoácidos , Animais , Humanos , Inflamação/genética , Dados de Sequência Molecular , Processamento de Proteína Pós-Traducional
3.
Methods Enzymol ; 490: 175-94, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21266251

RESUMO

Activating transcription factor 3 (ATF3) gene encodes a member of the ATF family of transcription factors and is induced by various stress signals, including many of those that induce the unfolded protein response (UPR). Emerging evidence suggests that ATF3 is a hub of the cellular adaptive-response network and studies using various mouse models indicate that ATF3 plays a role in the pathogenesis of various diseases. One way to investigate the potential relevance of ATF3 to human diseases is to determine its expression in patient samples and test whether it correlates with disease progression or clinical outcomes. Due to the scarcity and preciousness of patient samples, methods that can detect ATF3 on archival tissue sections would greatly facilitate this research. In this chapter, we briefly review the roles of ATF3 in cellular adaptive-response and UPR, and then describe the detailed steps and tips that we developed based on general immunohistochemistry (IHC) protocols to detect ATF3 on paraffin embedded sections.


Assuntos
Fator 3 Ativador da Transcrição/metabolismo , Imuno-Histoquímica/métodos , Fator 3 Ativador da Transcrição/genética , Animais , Modelos Animais de Doenças , Humanos , Imuno-Histoquímica/instrumentação , Imuno-Histoquímica/normas , Camundongos , Camundongos Knockout , Projetos Piloto , Sensibilidade e Especificidade , Estresse Fisiológico/fisiologia , Fixação de Tecidos/instrumentação , Fixação de Tecidos/métodos , Resposta a Proteínas não Dobradas/fisiologia
4.
Diabetes ; 57(3): 635-44, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18057093

RESUMO

OBJECTIVE: beta-Cell failure is an essential component of all types of diabetes, and the insulin receptor substrate 2 (IRS2) branch of signaling plays a key role in beta-cell survival and function. We tested the hypothesis that activating transcription factor 3 (ATF3), a stress-inducible proapoptotic gene, downregulates the expression of IRS2 in beta-cells. RESEARCH DESIGN AND METHODS: We used both the gain- and loss-of-function approaches to test the effects of ATF3 on IRS2 gene expression. We also analyzed the binding of ATF3 to the IRS2 promoter by chromatin immunoprecipitation assay and the transcription of the IRS2 gene by polymerase II occupancy assay. Furthermore, we tested the ability of IRS2 to alleviate the proapoptotic effects of ATF3 in cultured beta-cells and in transgenic mice using the rat insulin promoter to drive the transgenes. RESULTS: Expression of ATF3 is sufficient to reduce IRS2 gene expression; in contrast, knockdown or knockout of ATF3 reduces the ability of stress signals to downregulate IRS2 expression. ATF3 binds to the IRS2 promoter in vivo, and the binding of ATF3 correlates with decreased IRS2 gene transcription. Functionally, expression of IRS2 protects beta-cells from ATF3-induced apoptosis. CONCLUSIONS: IRS2 is a target gene of ATF3, and its repression by ATF3 contributes, at least partly, to the apoptosis induced by ATF3. Because ATF3 is a stress-inducible gene, our work provides a direct link to explain how environmental stress factors can modulate IRS2 gene transcription.


Assuntos
Fator 3 Ativador da Transcrição/metabolismo , Apoptose/fisiologia , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fosfoproteínas/metabolismo , Fator 3 Ativador da Transcrição/genética , Animais , Linhagem Celular , Células Cultivadas , Regulação para Baixo , Insulina/metabolismo , Proteínas Substratos do Receptor de Insulina , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Camundongos Knockout , Fosfoproteínas/genética , Regiões Promotoras Genéticas/genética , Regiões Promotoras Genéticas/fisiologia , Ratos , Estresse Fisiológico , Fatores de Tempo
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