Insulin-like growth factor binding protein-6 delays replicative senescence of human fibroblasts

• Published in: Mechanisms of ageing and development Vol. 132; no. 10; pp. 468 - 479
• Main Authors: Micutkova, Lucia, Diener, Thomas, Li, Chen, Rogowska-Wrzesinska, Adelina, Mueck, Christoph, Huetter, Eveline, Weinberger, Birgit, Grubeck-Loebenstein, Beatrix, Roepstorff, Peter, Zeng, Rong, Jansen-Duerr, Pidder
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 01.10.2011; Elsevier; Elsevier Science Ireland
• Subjects: Adult; Aged; Aging - blood; Amino Acid Sequence; Apoptosis - genetics; Apoptosis - physiology; Base Sequence; Biological and medical sciences; Cell Proliferation; Cell Survival - genetics; Cell Survival - physiology; Cells, Cultured; Cellular Senescence - genetics; Cellular Senescence - physiology; Development. Metamorphosis. Moult. Ageing; DNA Primers - genetics; Down-Regulation; Fibroblast; Fibroblasts - cytology; Fibroblasts - physiology; Fundamental and applied biological sciences. Psychology; Gene Knockdown Techniques; Humans; IGFBP-6; Insulin-Like Growth Factor Binding Protein 6 - antagonists & inhibitors; Insulin-Like Growth Factor Binding Protein 6 - genetics; Insulin-Like Growth Factor Binding Protein 6 - physiology; Molecular Sequence Data; Proteomics; Real-Time Polymerase Chain Reaction; RNA, Small Interfering - genetics; Secretome; Senescence; Up-Regulation; Vertebrates: anatomy and physiology, studies on body, several organs or systems; LC-MS/MS; Senescence; IGFBP-6; Proteomics; IGF; Secretome; SASP; Fibroblast; Human; Insulin like growth factor binding protein; Vertebrata; Mammalia
• ISSN: 0047-6374; 1872-6216
• DOI: 10.1016/j.mad.2011.07.005

► Proteomic analysis of senescent secretome reveals upregulation of IGFBP-6 in fibroblasts. ► IGFBP-6 knockdown induces premature senescence in young fibroblasts. ► IGFBP-6 lentiviral overexpression delays replicative senescence in fibroblasts. Cellular senescence can be induced by a variety of mechanisms, and recent data suggest a key role for cytokine networks to maintain the senescent state. Here, we have used a proteomic LC-MS/MS approach to identify new extracellular regulators of senescence in human fibroblasts. We identified 26 extracellular proteins with significantly different abundance in conditioned media from young and senescent fibroblasts. Among these was insulin-like growth factor binding protein-6 (IGFBP-6), which was chosen for further analysis. When IGFBP-6 gene expression was downregulated, cell proliferation was inhibited and apoptotic cell death was increased. Furthermore, downregulation of IGFBP-6 led to premature entry into cellular senescence. Since IGFBP-6 overexpression increased cellular lifespan, the data suggest that IGFBP-6, in contrast to other IGF binding proteins, is a negative regulator of cellular senescence in human fibroblasts.