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Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis

Nature volume 413, pages 86–91 (2001)Cite this article

Abstract

The cyclin-dependent kinase inhibitor p16INK4a can induce senescence of human cells, and its loss by deletion, mutation or epigenetic silencing is among the most frequently observed molecular lesions in human cancer1,2. Overlapping reading frames in the INK4A/ARF gene encode p16INK4a and a distinct tumour-suppressor protein, p19ARF (ref. 3). Here we describe the generation and characterization of a p16Ink4a-specific knockout mouse that retains normal p19Arf function. Mice lacking p16Ink4a were born with the expected mendelian distribution and exhibited normal development except for thymic hyperplasia. T cells deficient in p16Ink4a exhibited enhanced mitogenic responsiveness, consistent with the established role of p16Ink4a in constraining cellular proliferation. In contrast to mouse embryo fibroblasts (MEFs) deficient in p19Arf (ref. 4), p16Ink4a-null MEFs possessed normal growth characteristics and remained susceptible to Ras-induced senescence. Compared with wild-type MEFs, p16Ink4a-null MEFs exhibited an increased rate of immortalization, although this rate was less than that observed previously for cells null for Ink4a/Arf, p19Arf or p53 (refs 4, 5). Furthermore, p16Ink4a deficiency was associated with an increased incidence of spontaneous and carcinogen-induced cancers. These data establish that p16Ink4a, along with p19Arf, functions as a tumour suppressor in mice.

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Figure 1: Deletion of p16Ink4a.
Figure 2: Growth of p16Ink4a-null cells.
Figure 3: p16Ink4a-null mice are tumour prone.
Figure 4: Methylation of p16Ink4a in tumours.

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Acknowledgements

We thank E. Farazi, S. Chan, M. Sinha, S. Alson and the Dana Farber Cancer Institute Mouse Core for experimental advice and assistance. We also thank H. Westphal, T. Devereux, M. Oren, M. Bosenberg, D. Silver and A. Buchmann for advice or reagents, and L. Chin, J. DeCaprio, W. Kaelin and P. Sicinski for comments on the manuscript. N.E.S. is an Howard Hughes Medical Institute Physician Postdoctoral Fellow; N.B. is supported by the American Cancer Society John Peter Hoffman Award; K.H.L. is supported by the National Nuclear R and D Program and Human Genome Program from the Korean Ministry of Science and Technology; D.H.C. is supported by a Physician Scientist Fellowship of the Damon Runyon–Walter Winchell Foundation; and R.A.D. is an American Cancer Society Professor and recipient of the Steven and Michele Kirsch Foundation Investigator Award. This work was supported by grants from the National Institutes of Health, the National Cancer Institute and the American Cancer Society.

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Author notes

  1. Daniel Carrasco & Diego H. Castrillon

    Present address: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA

  2. Kee-Ho Lee

    Present address: Laboratory of Molecular Oncology, Korea Cancer Center Hospital, Seoul, 139-706, Korea

Authors and Affiliations

  1. Departments of Adult Oncology, Medicine and Genetics, Harvard Medical School and the Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA

    Norman E. Sharpless, Nabeel Bardeesy, Kee-Ho Lee, Daniel Carrasco, Diego H. Castrillon, Andrew J. Aguirre, Emily A. Wu, James W. Horner & Ronald A. DePinho

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  1. Norman E. Sharpless
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Correspondence to Ronald A. DePinho.

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Sharpless, N., Bardeesy, N., Lee, KH. et al. Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. Nature 413, 86–91 (2001). https://doi.org/10.1038/35092592

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