| | |  | | | | Record from Web of Science® | | | | | | |
| Oncogene-induced senescence as an initial barrier in lymphoma development |
|
|
| Author(s): Braig M, Lee S, Loddenkemper C, Rudolph C, Peters AHFM, Schlegelberger B, Stein H, Dorken B, Jenuwein T, Schmitt CA |
| Source: NATURE Volume: 436 Issue: 7051 Pages: 660-665 Published: AUG 4 2005 |
| Times Cited: 257 References: 31 |
| 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 E mu-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. |
| Document Type: Article |
| Language: English |
| Reprint Address: Schmitt, CA (reprint author), Charite Univ Med Berlin Haematol Oncol, D-13353 Berlin, Germany |
Addresses:
1. Charite Univ Med Berlin Haematol Oncol, D-13353 Berlin, Germany
2. Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany
3. Res Inst Mol Pathol, A-1030 Vienna, Austria
4. Friedrich Miescher Inst Biomed Res, CH-4058 Basel, Switzerland
5. Hannover Med Sch, Inst Cell & Mol Pathol, D-30625 Hannover, Germany
6. Charite Univ Med Berlin, Dept Pathol, D-12200 Berlin, Germany |
| Publisher: NATURE PUBLISHING GROUP, MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND |
| Subject Category: Multidisciplinary Sciences |
| IDS Number: 951XA |
| ISSN: 0028-0836 |
| DOI: 10.1038/nature03841 |
|
| | | | | | | | | Record from Web of Science® | | | | | | | | | |