Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis.
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 cancer. 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.
Sharpless
N E
NE
Departments of Adult Oncology, Medicine and Genetics, Harvard Medical School and the Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Bardeesy
N
N
Lee
K H
KH
Carrasco
D
D
Castrillon
D H
DH
Aguirre
A J
AJ
Wu
E A
EA
Horner
J W
JW
DePinho
R A
RA
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D002273:Carcinogens; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D005260:Female; D005347:Fibroblasts / Q000502:physiology; D017353:Gene Deletion; D018390:Gene Targeting; D019942:Genes, p16; D020022:Genetic Predisposition to Disease; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics*; D011506:Proteins / Q000235:genetics* / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology; D013950:Thymus Gland / Q000473:pathology; D025803:Tumor Suppressor Protein p14ARF; D014520:Urethane
D002273:Carcinogens; D011506:Proteins; D025803:Tumor Suppressor Protein p14ARF; D014520:Urethane; D015127:9,10-Dimethyl-1,2-benzanthracene