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The differential impact of p16INK4a or p19ARF deficiency on cell growth and tumorigenesis

Oncogene volume 23, pages 379–385 (2004)Cite this article

Abstract

Mounting genetic evidence suggests that each product of the Ink4a/Arf locus, p16INK4a and p19ARF, possesses tumor-suppressor activity (Kamijo et al., 1997; Krimpenfort et al., 2001; Sharpless et al., 2001a). We report the generation and characterization of a p19ARF-specific knockout allele (p19ARF−/−) and direct comparison with mice and derivative cells deficient for p16INK4a, both p16INK4a and p19ARF, and p53. Like Ink4a/Arf−/− murine embryo fibroblasts (MEFs), p19ARF−/− MEFs were highly susceptible to oncogenic transformation, exhibited enhanced subcloning efficiency at low density, and resisted both RAS- and culture-induced growth arrest. In contrast, the biological profile of p16INK4a−/− MEFs in these assays more closely resembled that of wild-type cells. In vivo, however, both p19ARF−/− and p16INK4a−/− animals were significantly more tumor prone than wild-type animals, but each less so than p53−/− or Ink4a/Arf−/− animals, and with differing tumor spectra. These data confirm the predominant role of p19ARF over p16INK4a in cell culture-based assays of MEFs, yet also underscore the importance of the analysis of tumor suppressors across many cell types within the organism. The cancer-prone conditions of mice singly deficient for either p16INK4a or p19ARF agree with data derived from human cancer genetics, and reinforce the view that both gene products play significant and nonredundant roles in suppressing malignant transformation in vivo.

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Acknowledgements

We wish to thank R Carrasco and B Bachoo for assistance with mouse histopathology; C Torrice, S Alson, Aguirre, S Chan, K Chin, and J Horner for advice and reagents; and C Sherr and T Van Dyke for comments on the manuscript. This work was supported by grants from the Howard Hughes Medical Institute, National Institutes of Health and American Cancer Society. RAD is an American Cancer Society Research Professor. NES is a Sydney Kimmel Foundation for Cancer Research Scholar.

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Author notes

  1. Diego H Castrillon

    Present address: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA

Authors and Affiliations

  1. Departments of Medicine and Genetics, Lineberger Cancer Center, CB# 7295, The University of North Carolina School of Medicine, Chapel Hill, 27599-7295, NC, USA

    Norman E Sharpless, Matthew R Ramsey & Periasamy Balasubramanian

  2. Departments of Adult Oncology, Medicine and Genetics, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

    Diego H Castrillon & Ronald A DePinho

  3. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA

    Diego H Castrillon

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  1. Norman E Sharpless
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  2. Matthew R Ramsey
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Correspondence to Norman E Sharpless.

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Sharpless, N., Ramsey, M., Balasubramanian, P. et al. The differential impact of p16INK4a or p19ARF deficiency on cell growth and tumorigenesis. Oncogene 23, 379–385 (2004). https://doi.org/10.1038/sj.onc.1207074

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