Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis

Norman E. Sharpless, Nabeel Bardeesy, Kee-Ho Lee, Daniel Carrasco, Diego H. Castrillon, Andrew J. Aguirre, Emily A. Wu, James W. Horner and Ronald A. DePinho ()
Additional contact information
Norman E. Sharpless: Medicine and Genetics, Harvard Medical School and the Dana-Farber Cancer Institute
Nabeel Bardeesy: Medicine and Genetics, Harvard Medical School and the Dana-Farber Cancer Institute
Kee-Ho Lee: Medicine and Genetics, Harvard Medical School and the Dana-Farber Cancer Institute
Daniel Carrasco: Medicine and Genetics, Harvard Medical School and the Dana-Farber Cancer Institute
Diego H. Castrillon: Medicine and Genetics, Harvard Medical School and the Dana-Farber Cancer Institute
Andrew J. Aguirre: Medicine and Genetics, Harvard Medical School and the Dana-Farber Cancer Institute
Emily A. Wu: Medicine and Genetics, Harvard Medical School and the Dana-Farber Cancer Institute
James W. Horner: Medicine and Genetics, Harvard Medical School and the Dana-Farber Cancer Institute
Ronald A. DePinho: Medicine and Genetics, Harvard Medical School and the Dana-Farber Cancer Institute

Nature, 2001, vol. 413, issue 6851, 86-91

Abstract: 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.

Date: 2001
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/35092592 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:413:y:2001:i:6851:d:10.1038_35092592

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/35092592

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().