Cellular senescence or EGFR signaling induces Interleukin 6 (IL-6) receptor expression controlled by mammalian target of rapamycin (mTOR)
| Autor: | Jürgen Scheller, Annika Sommerfeld, Fabian Kuck, Roland P. Piekorz, Klaus Schulze-Osthoff, Stefan Rose-John, Philipp A. Lang, Mareike Kessenbrock, Christoph Garbers, Kirstin Konzak, Tak W. Mak, Frank Essmann, Dirk Brenner, Dieter Häussinger, Samadhi Aparicio-Siegmund |
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| Rok vydání: | 2013 |
| Předmět: |
Fetal Proteins
Senescence Biology mTORC2 Cell Line ADAM10 Protein Mice Downregulation and upregulation Report Animals Humans RNA Small Interfering Molecular Biology Cellular Senescence PI3K/AKT/mTOR pathway Mice Knockout Interleukin-6 TOR Serine-Threonine Kinases RPTOR PTEN Phosphohydrolase Membrane Proteins Cell Biology Receptors Interleukin-6 Cell biology ErbB Receptors Gene Expression Regulation Neoplastic ADAM Proteins Cell Transformation Neoplastic Interleukin-6 receptor Cancer research Amyloid Precursor Protein Secretases Signal transduction Carrier Proteins Microtubule-Associated Proteins Cell aging Signal Transduction Developmental Biology |
| Zdroj: | Cell Cycle. 12:3421-3432 |
| ISSN: | 1551-4005 1538-4101 |
| DOI: | 10.4161/cc.26431 |
| Popis: | Interleukin 6 (IL-6) signaling plays a role in inflammation, cancer, and senescence. Here, we identified soluble IL-6 receptor (sIL-6R) as a member of the senescence-associated secretory phenotype (SASP). Senescence-associated sIL-6R upregulation was mediated by mammalian target of rapamycin (mTOR). sIL-6R was mainly generated by a disintegrin and metalloprotease 10 (ADAM10)-dependent ectodomain shedding to enable IL-6 trans-signaling. In vivo, heterozygous PTEN-knockout mice exhibited higher mTOR activity and increased sIL-6R levels. Moreover, aberrant EGF receptor (EGFR) activation triggered IL-6 synthesis. In analogy to senescence, EGFR-induced activation of mTOR also induced IL-6R expression and sIL-6R generation. Hence, mTOR activation reprograms IL-6 non-responder cells into IL-6 responder cells. Our data suggest that mTOR serves as a central molecular switch to facilitate cellular IL-6 classic and trans-signaling via IL-6R upregulation with direct implications for cellular senescence and tumor development. |
| Databáze: | OpenAIRE |
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