Reference SummaryLatres E, EMBO J 2000 Jul 3;19(13):3496-506

Title

 Limited overlapping roles of P15(INK4b) and P18(INK4c) cell cycle inhibitors in proliferation and tumorigenesis

Authors

 Latres E; Malumbres M; Sotillo R; Martin J; Ortega S; Martin-Caballero J; Flores JM; Cordon-Cardo C; Barbacid M

Journal

 EMBO J

Volume

 19

Issue

 13

Year

 2000

Pages

 3496-506

Abstract

 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.

Links

 J:63299 – MGI References
10880462 – National Library of Medicine/PubMed

Models
Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
B6;129S1-Cdkn2ctm1Bbd Adrenal gland - Medulla pheochromocytoma Adrenal gland - Medulla

10
B6;129S1-Cdkn2btm1Bbd Cdkn2ctm1Bbd Adrenal gland - Medulla pheochromocytoma Adrenal gland - Medulla

2.5
B6;129S1-Cdkn2btm1Bbd Connective tissue - Fibroblast fibrosarcoma Skin

0.7
B6;129S1-Cdkn2ctm1Bbd Kidney carcinoma Kidney

1.7
B6;129S1-Cdkn2btm1Bbd Leukocyte - Lymphocyte - B-lymphocyte hyperplasia Lymph node

13
B6;129S1-Cdkn2btm1Bbd Leukocyte - Lymphocyte - B-lymphocyte hyperplasia Spleen

observed
B6;129S1-Cdkn2ctm1Bbd Leukocyte - Lymphocyte - B-lymphocyte lymphoma Leukocyte - Lymphocyte - B-lymphocyte

3.4
B6;129S1-Cdkn2btm1Bbd Leukocyte - Lymphocyte lymphoma Leukocyte - Lymphocyte

0.7
B6;129S1-Cdkn2ctm1Bbd Leukocyte - Lymphocyte lymphoma Thymus

1.7
B6;129S1-Cdkn2btm1Bbd Cdkn2ctm1Bbd Leukocyte tumor Leukocyte

5
B6;129S1-Cdkn2btm1Bbd Lung adenocarcinoma Lung

0.7
B6;129S1 Lung adenoma Lung

2.4
B6;129S1-Cdkn2ctm1Bbd Mammary gland hyperplasia Mammary gland

30
B6;129S1-Cdkn2btm1Bbd/+ Mesodermal cell/mesoblast sarcoma Mesodermal cell/mesoblast

1
B6;129S1-Cdkn2btm1Bbd Pancreas adenocarcinoma Pancreas

0.7
B6;129S1-Cdkn2btm1Bbd Cdkn2ctm1Bbd Pituitary gland - Pars intermedia adenoma Pituitary gland - Pars intermedia

48
B6;129S1-Cdkn2ctm1Bbd Pituitary gland hyperplasia Pituitary gland

high
B6;129S1 Pituitary gland tumor Pituitary gland

0
B6;129S1-Cdkn2ctm1Bbd Pituitary gland tumor Pituitary gland

40
B6;129S1-Cdkn2ctm1Bbd/+ Pituitary gland tumor Pituitary gland

0
B6;129S1-Cdkn2btm1Bbd Skin papilloma
  • ultraviolet-B radiation (UVB)
  • dimethylbenzanthracene (DMBA)
 Skin

4.5
B6;129S1 Skin papilloma
  • ultraviolet-B radiation (UVB)
  • dimethylbenzanthracene (DMBA)
 Skin

4.5
B6;129S1-Cdkn2btm1Bbd/+ Skin papilloma
  • ultraviolet-B radiation (UVB)
  • dimethylbenzanthracene (DMBA)
 Skin

2.6
B6;129S1-Cdkn2ctm1Bbd Testis tumor Testis

observed
B6;129S1-Cdkn2btm1Bbd Cdkn2ctm1Bbd Testis tumor Testis

4.2
B6;129S1-Cdkn2btm1Bbd (Unspecified organ) angiosarcoma (Unspecified organ)

5.2
B6;129S1-Cdkn2ctm1Bbd (Unspecified organ) angiosarcoma (Unspecified organ)

3.4
B6;129S1-Cdkn2btm1Bbd Cdkn2ctm1Bbd (Unspecified organ) angiosarcoma (Unspecified organ)

observed