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Limited overlapping roles of P15 INK4b and P18 INK4c cell cycle inhibitors in proliferation and tumorigenesis
Author(s) -
Latres Esther,
Malumbres Marcos,
Sotillo Rocío,
Martín Javier,
Ortega Sagrario,
MartínCaballero Juan,
Flores Juana María,
CordónCardo Carlos,
Barbacid Mariano
Publication year - 2000
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/19.13.3496
Subject(s) - biology , carcinogenesis , cell cycle , cell growth , microbiology and biotechnology , cancer research , computational biology , genetics , cell , gene
Entry of quiescent cells into the cell cycle is driven by the cyclin D‐dependent kinases Cdk4 and Cdk6. These kinases are negatively regulated by the INK4 cell cycle inhibitors. We report the generation of mice defective in P15 INK4b and P18 INK4c . Ablation of these genes, either alone or in combination, does not abrogate cell contact inhibition or senescence of mouse embryo fibroblasts in culture. However, loss of P15 INK4b , but not of P18 INK4c , confers proliferative advantage to these cells and makes them more sensitive to transformation by H‐ ras oncogenes. In vivo , ablation of P15 INK4b and P18 INK4c genes results in lymphoproliferative disorders and tumor formation. Mice lacking P18 INK4c have deregulated epithelial cell growth leading to the formation of cysts, mostly in the cortical region of the kidneys and the mammary epithelium. Loss of both P15 INK4b and P18 INK4c does not result in significantly distinct phenotypic manifestations except for the appearance of cysts in additional tissues. These results indicate that P15 INK4b and P18 IKN4c are tumor suppressor proteins that act in different cellular lineages and/or pathways with limited compensatory roles.