Reference SummarySotillo R, EMBO J 2001 Dec 3;20(23):6637-47

Title

 Wide spectrum of tumors in knock-in mice carrying a Cdk4 protein insensitive to INK4 inhibitors.

Authors

 Sotillo R; Dubus P; Martin J; de la Cueva E; Ortega S; Malumbres M; Barbacid M

Journal

 EMBO J

Volume

 20

Issue

 23

Year

 2001

Pages

 6637-47

Abstract

 We have introduced a point mutation in the first coding exon of the locus encoding the cyclin-dependent kinase 4 (Cdk4) by homologous recombination in embryonic stem cells. This mutation (replacement of Arg24 by Cys) was first found in patients with hereditary melanoma and renders Cdk4 insensitive to INK4 inhibitors. Here, we report that primary embryonic fibroblasts expressing the mutant Cdk4R24C kinase are immortal and susceptible to transformation by Ras oncogenes. Moreover, homozygous Cdk4(R24C/R24C) mutant mice develop multiple tumors with almost complete penetrance. The most common neoplasia (endocrine tumors and hemangiosarcomas) are similar to those found in pRb(+/-) and p53(-/-) mice. This Cdk4 mutation cooperates with p53 and p27(Kip1) deficiencies in decreasing tumor latency and favoring development of specific tumor types. These results provide experimental evidence for a central role of Cdk4 regulation in cancer and provide a valuable model for testing the potential anti-tumor effect of Cdk4 inhibitors in vivo.

Links

 J:73034 – MGI References
11726500 – National Library of Medicine/PubMed

Models
Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
CD-1;129-Cdk4tm1.1Bbd Adipose tissue lipoma Adipose tissue

observed
CD-1;129-Cdk4tm1.1Bbd Adipose tissue liposarcoma Adipose tissue

observed
CD-1;129-Cdk4tm1.1Bbd Adrenal gland - Subcapsular cell lesion Adrenal gland - Subcapsular cell

very low
CD-1;129-Cdk4tm1.1Bbd Blood vessel hemangiosarcoma Blood vessel

22 - 56
[not specified]-Cdk4tm1.1Bbd Trp53tm1Tyj Blood vessel hemangiosarcoma Blood vessel

observed
CD-1;129-Cdk4tm1.1Bbd Bone osteoma Bone

observed
CD-1;129-Cdk4tm1.1Bbd Bone osteosarcoma Bone

observed
CD-1;129-Cdk4tm1.1Bbd Connective tissue - Fibroblast fibrosarcoma Connective tissue - Fibroblast

observed
[not specified]-Cdk4tm1.1Bbd Trp53tm1Tyj Germ cell (sex not specified) teratoma Germ cell (sex not specified)

9.8
[not specified]-Cdk4tm1.1Bbd/+ Trp53tm1Tyj Germ cell (sex not specified) teratoma Germ cell (sex not specified)

0
[not specified]-Trp53tm1Tyj Germ cell (sex not specified) teratoma Germ cell (sex not specified)

0
CD-1;129-Cdk4tm1.1Bbd Intestine tumor Intestine

observed
CD-1;129-Cdk4tm1.1Bbd Kidney tumor Kidney

observed
[not specified]-Cdk4tm1.1Bbd Trp53tm1Tyj Leukocyte - Lymphocyte - B-lymphocyte lymphoma - diffuse large cell (DLCL) Spleen

observed
CD-1;129-Cdk4tm1.1Bbd Leukocyte - Lymphocyte hyperplasia Spleen

6.0
CD-1;129-Cdk4tm1.1Bbd Leukocyte - Lymphocyte hyperplasia Lymph node

13
CD-1;129-Cdk4tm1.1Bbd Leukocyte - Myelocyte (Granulocyte) - Basophil - Mast cell tumor Leukocyte - Myelocyte (Granulocyte) - Basophil - Mast cell

1.0 - 2.0
CD-1;129-Cdk4tm1.1Bbd Leukocyte - Myelocyte (Granulocyte) metaplasia Leukocyte - Myelocyte (Granulocyte)

13
CD-1;129-Cdk4tm1.1Bbd Leukocyte lymphoma Leukocyte

0 - 1.9
[not specified]-Cdk4tm1.1Bbd Trp53tm1Tyj Leukocyte lymphoma Leukocyte

51
[not specified]-Cdk4tm1.1Bbd/+ Trp53tm1Tyj Leukocyte lymphoma Leukocyte

73
[not specified]-Trp53tm1Tyj Leukocyte lymphoma Leukocyte

82
CD-1;129-Cdk4tm1.1Bbd Liver - Hepatocyte lesion Liver - Hepatocyte

very low
CD-1;129-Cdk4tm1.1Bbd Liver hepatocellular adenoma Liver

observed
CD-1;129-Cdk4tm1.1Bbd Liver hepatocellular tumor Liver

0 - 20
CD-1;129-Cdk4tm1.1Bbd Lung adenocarcinoma Lung

observed
CD-1;129-Cdk4tm1.1Bbd Lung adenoma Lung

observed
CD-1;129-Cdk4tm1.1Bbd Lung tumor Lung

18 - 32
CD-1;129-Cdk4tm1.1Bbd Mammary gland lesion Mammary gland

very low
CD-1;129-Cdk4tm1.1Bbd Mesodermal cell/mesoblast sarcoma Mesodermal cell/mesoblast

26 - 62
[not specified]-Cdk4tm1.1Bbd Trp53tm1Tyj Mesodermal cell/mesoblast sarcoma Mesodermal cell/mesoblast

49
[not specified]-Cdk4tm1.1Bbd/+ Trp53tm1Tyj Mesodermal cell/mesoblast sarcoma Mesodermal cell/mesoblast

40
[not specified]-Trp53tm1Tyj Mesodermal cell/mesoblast sarcoma Mesodermal cell/mesoblast

18
CD-1;129-Cdk4tm1.1Bbd Mesodermal cell/mesoblast sarcoma - undifferentiated Mesodermal cell/mesoblast

observed
CD-1;129-Cdk4tm1.1Bbd Mesodermal cell/mesoblast tumor Mesodermal cell/mesoblast

32 - 68
CD-1;129-Cdk4tm1.1Bbd Mesodermal cell/mesoblast tumor - benign Mesodermal cell/mesoblast

6.0 - 7.6
[not specified]-Cdk4tm1.1Bbd Trp53tm1Tyj Muscle - Smooth leiomyosarcoma Muscle - Smooth

observed
CD-1;129-Cdk4tm1.1Bbd Ovary - Granulosa cell tumor Ovary - Granulosa cell

observed
CD-1;129-Cdk4tm1.1Bbd Pancreas - Islet of Langerhans - Beta cell tumor Pancreas - Islet of Langerhans - Beta cell

30 - 42
CD-1;129-Cdk4tm1.1Bbd Pancreas - Islet of Langerhans adenoma Pancreas - Islet of Langerhans

observed
CD-1;129-Cdk4tm1.1Bbd Pancreas - Islet of Langerhans hyperplasia Pancreas - Islet of Langerhans

observed
CD-1;129-Cdk4tm1.1Bbd Pituitary gland adenocarcinoma Pituitary gland

observed
CD-1;129-Cdk4tm1.1Bbd Pituitary gland adenoma Pituitary gland

observed
CD-1;129-Cdk4tm1.1Bbd Pituitary gland tumor Pituitary gland

6.0 - 22
[not specified]-Cdk4tm1.1Bbd Cdkn1btm1Mlf Pituitary gland tumor Pituitary gland

observed
[not specified]-Cdk4tm1.1Bbd/+ Cdkn1btm1Mlf Pituitary gland tumor Pituitary gland

observed
[not specified]-Cdk4tm1.1Bbd Cdkn1btm1Mlf/+ Pituitary gland tumor Pituitary gland

observed
[not specified]-Cdkn1btm1Mlf Pituitary gland tumor Pituitary gland

observed
CD-1;129-Cdk4tm1.1Bbd Prostate gland lesion Prostate gland

very low
CD-1;129-Cdk4tm1.1Bbd Salivary gland lesion Salivary gland

very low
CD-1;129-Cdk4tm1.1Bbd Skin - Melanocyte melanoma Skin - Melanocyte

0
[not specified]-Cdk4tm1.1Bbd Trp53tm1Tyj Testis - Germ cell teratoma Testis - Germ cell

observed
CD-1;129-Cdk4tm1.1Bbd Testis - Leydig cell (Interstitial cell) hyperplasia Testis - Leydig cell (Interstitial cell)

observed
CD-1;129-Cdk4tm1.1Bbd Testis - Leydig cell (Interstitial cell) tumor Testis - Leydig cell (Interstitial cell)

62 - 70
CD-1;129-Cdk4tm1.1Bbd Thyroid gland tumor Thyroid gland

observed
CD-1;129-Cdk4tm1.1Bbd Uterus - Endometrium lesion Uterus - Endometrium

very low
CD-1;129-Cdk4tm1.1Bbd (Unspecified organ) histiocytoma - fibrous - malignant (Unspecified organ)

observed
CD-1;129-Cdk4tm1.1Bbd (Unspecified organ) lymphohematopoietic neoplasm (Unspecified organ)

2.0 - 2.9
CD-1;129-Cdk4tm1.1Bbd (Unspecified organ) tumor (Unspecified organ)

95 - 100
CD-1;129 (Unspecified organ) tumor (Unspecified organ)

0
CD-1;129-Cdk4tm1.1Bbd/+ (Unspecified organ) tumor (Unspecified organ)

observed
[not specified]-Cdk4tm1.1Bbd Trp53tm1Tyj (Unspecified organ) tumor (Unspecified organ)

100
[not specified]-Cdk4tm1.1Bbd/+ Trp53tm1Tyj (Unspecified organ) tumor (Unspecified organ)

100
[not specified]-Trp53tm1Tyj (Unspecified organ) tumor (Unspecified organ)

100