Reference SummarySotillo R, Proc Natl Acad Sci U S A 2001 Nov 6;98(23):13312-7

Title

 Invasive melanoma in Cdk4-targeted mice.

Authors

 Sotillo R; Garcia JF; Ortega S; Martin J; Dubus P; Barbacid M; Malumbres M

Journal

 Proc Natl Acad Sci U S A

Volume

 98

Issue

 23

Year

 2001

Pages

 13312-7

Abstract

 Many human tumors harbor mutations that result in deregulation of Cdk4 activity. Most of these mutations involve overexpression of D-type cyclins and inactivation of INK4 inhibitors. In addition, a mutation in the Cdk4 protein has been described in patients with familial melanoma (Wolfel, T., Hauer, M., Schneider, J., Serrano, M., Wolfel, C., et al. (1995) Science 269, 1281-1284; Zuo, L., Weger, J., Yang, Q., Goldstein, A. M., Tucker, M. A., et al. (1996) Nat. Genet. 12, 97-99). This mutation, R24C, renders the Cdk4 protein insensitive to inhibition by INK4 proteins including p16(INK4a), a major candidate for the melanoma susceptibility locus. Here we show that knock-in mice expressing a Cdk4 R24C allele are highly susceptible to melanoma development after specific carcinogenic treatments. These tumors do not have mutations in the p19(ARF)/p53 pathway, suggesting a specific involvement of the p16(INK4a)/Cdk4/Rb pathway in melanoma development. Moreover, by using targeted mice deficient for other INK4 inhibitors, we show that deletion of p18(INK4c) but not of p15(INK4b) confers proliferative advantage to melanocytic tumor growth. These results provide an experimental scenario to study the role of Cdk4 regulation in melanoma and to develop novel therapeutic approaches to control melanoma progression.

Links

 J:72579 – MGI References
11606789 – National Library of Medicine/PubMed

Strain Notes

Strain Note
B6.129S1-Cdkn2btm1Bbd This reference claims that these mice are on a "pure C57BL/6J genetic background", but since mice carrying this mutation were generated using 129S1-derived ES cells, they must be congenic.
B6.129S1-Cdkn2ctm1Bbd This reference claims that these mice are on a "pure C57BL/6J genetic background", but since mice carrying this mutation were generated using 129S1-derived ES cells, they must be congenic.
B6.Cg-Cdkn2atm1Rdp This reference claims that these mice are on a "pure C57BL/6J genetic background", but since mice carrying this mutation were generated using ES cells that contained a mixture of strains (75% 129/Sv, 20% C57BL/6J, 5% SJL), they must be congenic.

Models
Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
CD-1;129 Leukocyte lymphoma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
 Leukocyte

13
CD-1;129-Cdk4tm1.1Bbd Leukocyte lymphoma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
 Leukocyte

20
B6.Cg-Cdkn2atm1Rdp Leukocyte lymphoma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
 Leukocyte

100
B6.129S1-Cdkn2ctm1Bbd Leukocyte lymphoma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
 Leukocyte

70
CD-1;129-Cdk4tm1.1Bbd Mesodermal cell/mesoblast sarcoma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
 Mesodermal cell/mesoblast

observed
B6.129S1-Cdkn2ctm1Bbd Mesodermal cell/mesoblast sarcoma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
 Mesodermal cell/mesoblast

17
CD-1;129 Skin - Melanocyte melanoma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
 Skin - Melanocyte

0
CD-1;129-Cdk4tm1.1Bbd/+ Skin - Melanocyte melanoma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
 Skin - Melanocyte

observed
CD-1;129-Cdk4tm1.1Bbd Skin - Melanocyte melanoma Skin - Melanocyte

0
CD-1;129-Cdk4tm1.1Bbd Skin - Melanocyte melanoma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
 Skin - Melanocyte

70
CD-1;129-Cdk4tm1.1Bbd Skin - Melanocyte melanoma
  • ultraviolet-B radiation (UVB)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
 Skin - Melanocyte

observed
CD-1;129-Cdk4tm1.1Bbd Skin - Melanocyte melanoma
  • ultraviolet-B radiation (UVB)
 Skin - Melanocyte

0
B6.129S1-Cdkn2ctm1Bbd Skin - Melanocyte melanoma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
 Skin - Melanocyte

observed
CD-1;129 Skin lesion
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
 Skin

observed
CD-1;129-Cdk4tm1.1Bbd/+ Skin lesion
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
 Skin

very high
CD-1;129-Cdk4tm1.1Bbd Skin lesion
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
 Skin

very high
CD-1;129-Cdk4tm1.1Bbd Skin lesion
  • 7,12-dimethylbenz[a]anthracene (DMBA)
 Skin

observed
B6.Cg-Cdkn2atm1Rdp Skin lesion
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
 Skin

0
B6.129S1-Cdkn2btm1Bbd Skin lesion
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
 Skin

observed
B6.129S1-Cdkn2ctm1Bbd Skin lesion
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
 Skin

very high
C57BL/6J Skin lesion
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
 Skin

observed
CD-1;129 Skin papilloma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
 Skin

very high
CD-1;129-Cdk4tm1.1Bbd/+ Skin papilloma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
 Skin

very high
CD-1;129-Cdk4tm1.1Bbd Skin papilloma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
 Skin

very high
B6.129S1-Cdkn2btm1Bbd Skin papilloma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
 Skin

very high
B6.129S1-Cdkn2ctm1Bbd Skin papilloma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
 Skin

very high
C57BL/6J Skin papilloma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
 Skin

very high
CD-1;129 Skin squamous cell carcinoma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
 Skin

0
CD-1;129-Cdk4tm1.1Bbd Skin squamous cell carcinoma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
 Skin

15
CD-1;129-Cdk4tm1.1Bbd (Unspecified organ) carcinoma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
 (Unspecified organ)

observed