Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis

Zhenbang Chen, Lloyd C. Trotman, David Shaffer, Hui-Kuan Lin, Zohar A. Dotan, Masaru Niki, Jason A. Koutcher, Howard I. Scher, Thomas Ludwig, William Gerald, Carlos Cordon-Cardo and Pier Paolo Pandolfi ()
Additional contact information
Zhenbang Chen: Cancer Biology and Genetics Program
Lloyd C. Trotman: Cancer Biology and Genetics Program
David Shaffer: Cancer Biology and Genetics Program
Hui-Kuan Lin: Cancer Biology and Genetics Program
Zohar A. Dotan: Cancer Biology and Genetics Program
Masaru Niki: Cancer Biology and Genetics Program
Jason A. Koutcher: Sloan-Kettering Institute
Howard I. Scher: Sloan-Kettering Institute
Thomas Ludwig: Columbia University
William Gerald: Department of Pathology
Carlos Cordon-Cardo: Department of Pathology
Pier Paolo Pandolfi: Cancer Biology and Genetics Program

Nature, 2005, vol. 436, issue 7051, 725-730

Abstract: Cell senescence and cancer Cellular senescence, a growth-arrest program that limits the lifespan of mammalian cells and prevents unlimited cell proliferation, is attracting considerable interest because of its links to tumour suppression. Using a mouse model in which the oncogene Ras is activated in the haematopoietic compartment of bone marrow, Braig et al. show that cellular senescence can block lymphoma development. Genetic inactivation of the histone methyltransferase Suv39h1 that controls senescence by ‘epigenetic’ modification of DNA-associated proteins, or a pharmacological approach that mimics loss of this enzyme, allow the formation of malignant lymphomas in response to oncogenic Ras. This work has important implications for both tumour development and tumour therapy. Michaloglou et al. report that oncogene-induced senescence may be a physiologically important process in humans, keeping moles in a benign state for many years: unchecked they develop into malignant melanomas. Chen et al. also find that cellular senescence blocks tumorigenesis in vivo: they show that acting together, the p53 tumour suppressor and the cellular senescence system can prevent prostate cancer induction in mice by the PTEN mutation. Collado et al. show that cellular senescence is a defining feature of Ras-initiated premalignant tumours; this could prove valuable in the diagnosis and prognosis of cancer. See the web focus .

Date: 2005
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DOI: 10.1038/nature03918

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