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  • 1
    Keywords: EXPRESSION ; GROWTH ; NF-KAPPA-B ; TUMOR PROGRESSION ; p53 ; PANCREATIC-CANCER ; TUMORIGENESIS ; p16(INK4A) ; TGF-BETA ; DIPLOID CELL STRAINS
    Abstract: Oncogene-induced senescence (OIS) is crucial for tumour suppression. Senescent cells implement a complex pro-inflammatory response termed the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence, activates immune surveillance and paradoxically also has pro-tumorigenic properties. Here, we present evidence that the SASP can also induce paracrine senescence in normal cells both in culture and in human and mouse models of OIS in vivo. Coupling quantitative proteomics with small-molecule screens, we identified multiple SASP components mediating paracrine senescence, including TGF-beta family ligands, VEGF, CCL2 and CCL20. Amongst them, TGF-beta ligands play a major role by regulating p15(INK4b) and p21(CIP1). Expression of the SASP is controlled by inflammasome-mediated IL-1 signalling. The inflammasome and IL-1 signalling are activated in senescent cells and IL-1alpha expression can reproduce SASP activation, resulting in senescence. Our results demonstrate that the SASP can cause paracrine senescence and impact on tumour suppression and senescence in vivo.
    Type of Publication: Journal article published
    PubMed ID: 23770676
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  • 2
    Publication Date: 2011-11-15
    Description: Murine epidermal stem cells undergo alternate cycles of dormancy and activation, fuelling tissue renewal. However, only a subset of stem cells becomes active during each round of morphogenesis, indicating that stem cells coexist in heterogeneous responsive states. Using a circadian-clock reporter-mouse model, here we show that the dormant hair-follicle stem cell niche contains coexisting populations of cells at opposite phases of the clock, which are differentially predisposed to respond to homeostatic cues. The core clock protein Bmal1 modulates the expression of stem cell regulatory genes in an oscillatory manner, to create populations that are either predisposed, or less prone, to activation. Disrupting this clock equilibrium, through deletion of Bmal1 (also known as Arntl) or Per1/2, resulted in a progressive accumulation or depletion of dormant stem cells, respectively. Stem cell arrhythmia also led to premature epidermal ageing, and a reduction in the development of squamous tumours. Our results indicate that the circadian clock fine-tunes the temporal behaviour of epidermal stem cells, and that its perturbation affects homeostasis and the predisposition to tumorigenesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Janich, Peggy -- Pascual, Gloria -- Merlos-Suarez, Anna -- Batlle, Eduard -- Ripperger, Jurgen -- Albrecht, Urs -- Cheng, Hai-Ying M -- Obrietan, Karl -- Di Croce, Luciano -- Benitah, Salvador Aznar -- England -- Nature. 2011 Nov 9;480(7376):209-14. doi: 10.1038/nature10649.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Genomic Regulation and UPF, 08003 Barcelona, Spain.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22080954" target="_blank"〉PubMed〈/a〉
    Keywords: ARNTL Transcription Factors/deficiency/genetics/metabolism ; Animals ; Carcinoma, Squamous Cell/genetics/pathology ; Cell Adhesion/genetics ; Cell Aging ; Cell Cycle/genetics ; Cells, Cultured ; Circadian Clocks/genetics/*physiology ; Circadian Rhythm/genetics/*physiology ; Cues ; Female ; Gene Expression Regulation/genetics ; Hair Follicle/*cytology ; Homeostasis/genetics/physiology ; Male ; Mice ; Mice, Knockout ; Skin Neoplasms/genetics/pathology ; Stem Cell Niche ; Stem Cells/*cytology/metabolism ; Transforming Growth Factor beta/genetics ; Wnt Signaling Pathway/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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