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- Title
Oncogene-induced senescence as an initial barrier in lymphoma development.
- Authors
Braig, Melanie; Soyoung Lee; Loddenkemper, Christoph; Rudolph, Cornelia; Peters, Antoine H. F. M.; Schlegelberger, Brigitte; Stein, Harald; Dörken, Bernd; Jenuwein, Thomas; Schmitt, Clemens 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 Eµ-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.
- Subjects
ONCOGENIC viruses; VIRUSES; AGING; LYMPHOMAS; CELL death; CELLS; RETINOBLASTOMA; NEUROBLASTOMA
- Publication
Nature, 2005, Vol 436, Issue 7051, p660
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature03841