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Cell Cycle. 2013 Nov 1;12(21):3421-32. doi: 10.4161/cc.26431. Epub 2013 Sep 18.

Cellular senescence or EGFR signaling induces Interleukin 6 (IL-6) receptor expression controlled by mammalian target of rapamycin (mTOR).

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1
Institute of Biochemistry and Molecular Biology II; Medical Faculty; Heinrich-Heine-University; Düsseldorf, Germany.

Abstract

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.

KEYWORDS:

EGFR; Interleukin 6; Interleukin 6-Receptor; SASP; mTOR; senescence

PMID:
24047696
PMCID:
PMC3895430
DOI:
10.4161/cc.26431
[Indexed for MEDLINE]
Free PMC Article

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