Suppression of Nucleotide Metabolism Underlies the Establishment and Maintenance of Oncogene-Induced Senescence

被引：220

作者：

Aird, Katherine M. ^{[1
]}

Zhang, Gao ^{[2
]}

Li, Hua ^{[1
]}

Tu, Zhigang ^{[1
]}

Bitler, Benjamin G. ^{[1
]}

Garipov, Azat ^{[1
]}

Wu, Hong ^{[3
]}

Wei, Zhi ^{[4
]}

Wagner, Stephan N. ^{[5
,6
]}

Herlyn, Meenhard ^{[2
]}

Zhang, Rugang ^{[1
]}

机构：

[1] Wistar Inst Anat & Biol, Wistar Inst Canc Ctr, Gene Express & Regulat Program, Philadelphia, PA 19104 USA

[2] Wistar Inst Anat & Biol, Wistar Inst Canc Ctr, Tumor Microenvironm & Metastasis Program, Philadelphia, PA 19104 USA

[3] Fox Chase Canc Ctr, Dept Pathol, Philadelphia, PA 19111 USA

[4] New Jersey Inst Technol, Dept Comp Sci, Newark, NJ 07102 USA

[5] Med Univ Vienna, Dept Dermatol, Div Immunol Allergy & Infect Dis, A-1090 Vienna, Austria

[6] Austrian Acad Sci, CeMM Res Ctr Mol Med, A-1090 Vienna, Austria

来源：

CELL REPORTS | 2013年 / 3卷 / 04期

基金：

奥地利科学基金会;

关键词：

PRIMARY HUMAN-CELLS; DNA-DAMAGE; RIBONUCLEOTIDE REDUCTASE; CELLULAR SENESCENCE; HETEROCHROMATIN FOCI; TARGET GENES; IN-VIVO; C-MYC; CANCER; EXPRESSION;

D O I：

10.1016/j.celrep.2013.03.004

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

Oncogene-induced senescence is characterized by a stable cell growth arrest, thus providing a tumor suppression mechanism. However, the underlying mechanisms for this phenomenon remain unknown. Here, we show that a decrease in growth arrest. The decrease in dNTP levels is caused by oncogene-induced repression of ribonucleotide reductase subunit M2 (RRM2), a rate-limiting protein in dNTP synthesis. This precedes the senescence-associated cell-cycle exit and coincides with the DNA damage response. Consistently, RRM2 down-regulation is both necessary and sufficient for senescence. Strikingly, suppression of nucleotide metabolism by RRM2 repression is also necessary for maintenance of the stable senescence-associated cell growth arrest. Furthermore, RRM2 repression correlates with senescence status in benign nevi and melanoma, and its knockdown drives senescence of melanoma cells. These data reveal the molecular basis whereby the stable growth arrest of oncogene-induced senescence is established and maintained through suppression of nucleotide metabolism.

引用

页码：1252 / 1265

页数：14

共 39 条

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The atypical E2F family member E2F7 couples the p53 and RB pathways during cellular senescence [J].