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PDK1 controls upstream PI3K expression and PIP3 generation.
Dieterle, A M; Böhler, P; Keppeler, H; Alers, S; Berleth, N; Drießen, S; Hieke, N; Pietkiewicz, S; Löffler, A S; Peter, C; Gray, A; Leslie, N R; Shinohara, H; Kurosaki, T; Engelke, M; Wienands, J; Bonin, M; Wesselborg, S; Stork, B.
Afiliación
  • Dieterle AM; Department of Internal Medicine I, University Hospital Tübingen, Tübingen, Germany.
  • Böhler P; Institute of Molecular Medicine, University Hospital Düsseldorf, Düsseldorf, Germany.
  • Keppeler H; Department of Internal Medicine I, University Hospital Tübingen, Tübingen, Germany.
  • Alers S; Department of Internal Medicine I, University Hospital Tübingen, Tübingen, Germany.
  • Berleth N; Institute of Molecular Medicine, University Hospital Düsseldorf, Düsseldorf, Germany.
  • Drießen S; Institute of Molecular Medicine, University Hospital Düsseldorf, Düsseldorf, Germany.
  • Hieke N; Institute of Molecular Medicine, University Hospital Düsseldorf, Düsseldorf, Germany.
  • Pietkiewicz S; Institute of Molecular Medicine, University Hospital Düsseldorf, Düsseldorf, Germany.
  • Löffler AS; Institute of Molecular Medicine, University Hospital Düsseldorf, Düsseldorf, Germany.
  • Peter C; Institute of Molecular Medicine, University Hospital Düsseldorf, Düsseldorf, Germany.
  • Gray A; Division of Cell Signaling and Immunology, College of Life Sciences, University of Dundee, Dundee, UK.
  • Leslie NR; Division of Cell Signaling and Immunology, College of Life Sciences, University of Dundee, Dundee, UK.
  • Shinohara H; Laboratory for Lymphocyte Differentiation, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan.
  • Kurosaki T; Laboratory for Lymphocyte Differentiation, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan.
  • Engelke M; Institute of Cellular and Molecular Immunology, University Hospital Göttingen, Göttingen, Germany.
  • Wienands J; Institute of Cellular and Molecular Immunology, University Hospital Göttingen, Göttingen, Germany.
  • Bonin M; Department of Medical Genetics, MFT Services, University Hospital Tübingen, Tübingen, Germany.
  • Wesselborg S; Institute of Molecular Medicine, University Hospital Düsseldorf, Düsseldorf, Germany.
  • Stork B; Institute of Molecular Medicine, University Hospital Düsseldorf, Düsseldorf, Germany.
Oncogene ; 33(23): 3043-53, 2014 Jun 05.
Article en En | MEDLINE | ID: mdl-23893244
The PI3K/PDK1/Akt signaling axis is centrally involved in cellular homeostasis and controls cell growth and proliferation. Due to its key function as regulator of cell survival and metabolism, the dysregulation of this pathway is manifested in several human pathologies including cancers and immunological diseases. Thus, current therapeutic strategies target the components of this signaling cascade. In recent years, numerous feedback loops have been identified that attenuate PI3K/PDK1/Akt-dependent signaling. Here, we report the identification of an additional level of feedback regulation that depends on the negative transcriptional control of phosphatidylinositol 3-kinase (PI3K) class IA subunits. Genetic deletion of 3-phosphoinositide-dependent protein kinase 1 (PDK1) or the pharmacological inhibition of its downstream effectors, that is, Akt and mammalian target of rapamycin (mTOR), relieves this suppression and leads to the upregulation of PI3K subunits, resulting in enhanced generation of phosphatidylinositol-3,4,5-trisphosphate (PIP3). Apparently, this transcriptional induction is mediated by the concerted action of different transcription factor families, including the transcription factors cAMP-responsive element-binding protein and forkhead box O. Collectively, we propose that PDK1 functions as a cellular sensor that balances basal PIP3 generation at levels sufficient for survival but below a threshold being harmful to the cell. Our study suggests that the efficiency of therapies targeting the aberrantly activated PI3K/PDK1/Akt pathway might be increased by the parallel blockade of feedback circuits.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Serina-Treonina Quinasas / Fosfatos de Fosfatidilinositol / Fosfatidilinositol 3-Quinasas Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2014 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Serina-Treonina Quinasas / Fosfatos de Fosfatidilinositol / Fosfatidilinositol 3-Quinasas Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2014 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido