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Oncogene-induced senescence as an initial barrier in lymphoma development

Item Type:Article
Title:Oncogene-induced senescence as an initial barrier in lymphoma development
Creators Name:Braig, M. and Lee, S. and Loddenkemper, C. and Rudolph, C. and Peters, A.H. and Schlegelberger, B. and Stein, H. and Doerken, B. and Jenuwein, T. and Schmitt, C.A.
Abstract:Acute induction of oncogenic Ras provokes cellular senescence involving the retinoblastoma (Rb) pathway, but the tumour suppressive potential of senescence in vivo remains elusive. Recently, Rb-mediated silencing of growth-promoting genes by heterochromatin formation associated with methylation of histone H3 lysine 9 (H3K9me) was identified as a critical feature of cellular senescence, which may depend on the histone methyltransferase Suv39h1. Here we show that Emicro-N-Ras transgenic mice harbouring targeted heterozygous lesions at the Suv39h1, or the p53 locus for comparison, succumb to invasive T-cell lymphomas that lack expression of Suv39h1 or p53, respectively. By contrast, most N-Ras-transgenic wild-type ('control') animals develop a non-lymphoid neoplasia significantly later. Proliferation of primary lymphocytes is directly stalled by a Suv39h1-dependent, H3K9me-related senescent growth arrest in response to oncogenic Ras, thereby cancelling lymphomagenesis at an initial step. Suv39h1-deficient lymphoma cells grow rapidly but, unlike p53-deficient cells, remain highly susceptible to adriamycin-induced apoptosis. In contrast, only control, but not Suv39h1-deficient or p53-deficient, lymphomas senesce after drug therapy when apoptosis is blocked. These results identify H3K9me-mediated senescence as a novel Suv39h1-dependent tumour suppressor mechanism whose inactivation permits the formation of aggressive but apoptosis-competent lymphomas in response to oncogenic Ras.
Keywords:ADP-Ribosylation Factors, Apoptosis, Cell Aging, Neoplastic Cell Transformation, Chromosomal Instability, Animal Disease Models, Disease Progression, Neoplastic Gene Expression Regulation, ras Genes, Heterochromatin, Lymphoma, Methylation, Methyltransferases, Precancerous Conditions, Repressor Proteins, Transgenes, Biological Tumor Markers, Tumor Suppressor Protein p53, Animals, Mice
Publisher:Nature Publishing Group
Page Range:660-665
Date:4 August 2005
Official Publication:https://doi.org/10.1038/nature03841
PubMed:View item in PubMed

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