Oncogenic potential of cyclin E in T-cell lymphomagenesis in transgenic mice: evidence for cooperation between cyclin E and Ras but not Myc.

Abstract

To study the oncogenic activity of cyclin E in an in vivo system we generated transgenic mice expressing high levels of cyclin E in T-lymphocytes by using a construct containing the CD2 locus control region. These animals were neither predisposed to develop any tumors spontaneously nor showed an increased incidence when crossbred with Emu L-myc transgenic mice but developed hyperplasia in peripheral lymphoid organs at later age with an incidence of 27%. When treated with the DNA methylating carcinogen N-methylnitrosourea (MNU) that provokes the development of T-cell lymphomas, CD2-cyclin E transgenic animals came down with T-cell neoplasia showing a significant higher incidence (54%) than normal non transgenic controls (31%). In one of eight tumors that arose in normal MNU treated mice we could find an expected activating point mutation in the Ki-ras gene (12.5%). In contrast, the same mutation occurred in five of 16 tumors from CD2-cyclin E transgenic mice (31.2%). Whereas cyclin E overexpression alone did not lead to an increased CDK2 activity we observed in all tumors that emerged from either MNU treated normal mice or treated CD2-cyclin E transgenics a downregulation of p27KIP1 and a higher histone H1 kinase activity in CDK2 immunoprecipitates compared to normal tissue. These findings demonstrate that high level expression of cyclin E can predispose T-cells for hyperplasia and malignant transformation. However, the results also suggest that this activity of cyclin E is manifest only when other cooperating oncogenes in particular ras genes are present and activated. This would be consistent with our previous finding that cyclin E and Ha-Ras cooperate in focus formation assays in rat embryo fibroblasts.

• Authors: H Karsunky, C Geisen, T Schmidt, K Haas, B Zevnik, E Gau, T Möröy
• Journal: Oncogene (Oncogene) Vol. 18 Issue 54 Pg. 7816-24 (Dec 16 1999) ISSN: 0950-9232 [Print] England
• PMID: 10618723 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclin E
• Ionomycin
• Methylnitrosourea
• Protamine Kinase
• Tetradecanoylphorbol Acetate

Topics

• Animals
• Cell Transformation, Neoplastic
• Cyclin E (genetics)
• Embryo, Mammalian
• Fibroblasts
• Genes, myc
• Genes, ras
• Hyperplasia
• Ionomycin (pharmacology)
• Locus Control Region
• Lymphoid Tissue (drug effects, pathology)
• Lymphoma, T-Cell (chemically induced, genetics)
• Methylnitrosourea (toxicity)
• Mice
• Mice, Inbred C3H
• Mice, Inbred C57BL
• Mice, Transgenic
• Point Mutation
• Protamine Kinase (genetics, metabolism)
• Rats
• T-Lymphocytes (pathology, physiology)
• Tetradecanoylphorbol Acetate (toxicity)
• Thymus Gland (cytology, pathology)