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

Norman E. Sharpless, Matthew R. Ramsey, Periasamy Balasubramanian, Diego H. Castrillon, Ronald A. DePinho

Research output: Contribution to journalArticle

145 Citations (Scopus)

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 p19 ARF-specific knockout allele (p19ARF-/-) and direct comparison with mice and derivative cells deficient for p16INK4a, both p16INK4a and p19ARF, and p53. Like Ink4a/Arf-l- 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-l- and p16INK4a-l- 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.

Original languageEnglish (US)
Pages (from-to)379-385
Number of pages7
JournalOncogene
Volume23
Issue number2
DOIs
StatePublished - Jan 15 2004

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Carcinogenesis
Embryonic Structures
Growth
Fibroblasts
Neoplasms
Wild Animals
Medical Genetics
Cell Culture Techniques
Alleles
Genes

Keywords

  • cdkn2a
  • p14
  • p53
  • Rb

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

The differential impact of p16INK4a or p19ARF deficiency on cell growth and tumorigenesis. / Sharpless, Norman E.; Ramsey, Matthew R.; Balasubramanian, Periasamy; Castrillon, Diego H.; DePinho, Ronald A.

In: Oncogene, Vol. 23, No. 2, 15.01.2004, p. 379-385.

Research output: Contribution to journalArticle

Sharpless, NE, Ramsey, MR, Balasubramanian, P, Castrillon, DH & DePinho, RA 2004, 'The differential impact of p16INK4a or p19ARF deficiency on cell growth and tumorigenesis', Oncogene, vol. 23, no. 2, pp. 379-385. https://doi.org/10.1038/sj.onc.1207074
Sharpless, Norman E. ; Ramsey, Matthew R. ; Balasubramanian, Periasamy ; Castrillon, Diego H. ; DePinho, Ronald A. / The differential impact of p16INK4a or p19ARF deficiency on cell growth and tumorigenesis. In: Oncogene. 2004 ; Vol. 23, No. 2. pp. 379-385.
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