Malignant transformation by cyclin E and Ha-Ras correlates with lower sensitivity towards induction of cell death but requires functional Myc and CDK4

• Published in: Oncogene Vol. 15; no. 21; pp. 2615 - 2623
• Main Authors: HAAS, K, JOHANNES, C, GEISEN, C, SCHMIDT, T, KARSUNKY, H, BLASS-KAMPMANN, S, OBE, G, MÖRÖY, T
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 20.11.1997; Nature Publishing Group
• Subjects: Animals; Apoptosis; Biological and medical sciences; c-Myc protein; Carcinogens; Cell cycle; Cell death; Cell Line; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell Transformation, Neoplastic; Cyclin D; Cyclin D1; Cyclin E; Cyclin E - physiology; Cyclin-dependent kinase; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinases - physiology; Cyclins - physiology; DNA Damage; Embryo fibroblasts; Female; Fundamental and applied biological sciences. Psychology; G1 phase; Genes, ras; Genomic instability; Molecular and cellular biology; Myc protein; Polyploidy; Pregnancy; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-myc - physiology; Rats; Rats, Inbred F344; Transformed cells; Chromosomal aberration; Rat; Enzyme; Induction; Transferases; Rodentia; Malignant tumor; Cell transformation; Signal transduction; Vertebrata; Regulation(control); Mammalia; Cell line; Protein kinase; Malignant transformation; Cell cycle; Transcription factor; Fibroblast; Apoptosis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1201434

We demonstrate in this paper that the G1 phase specific cell cycle regulator cyclin E is able to provoke focus formation when cotransfected with activated Ha-ras into primary rat embryo fibroblasts (REFs). Cyclin E/Ha-ras transformed cells are highly tumorigenic in synergeneic rats, are able to form colonies in soft agar and show protection towards apoptosis upon serum starvation or DNA damage compared to cells transformed by the combination of Myc, cyclin D1 or SV40 large T-antigen and Ha-ras. Lines that were established after cyclin E/Ha-ras or cyclin D1/Ha-ras transformation contain a large percentage of polyploid cells. This was not observed in cells transformed with other oncoproteins and Ha-ras pointing to an involvement of D- and E type cyclins in genomic instability. The cyclin dependent kinase inhibitors p21 and p27 but also p16 completely abrogate focus formation by cyclin E and Ha-ras suggesting that the oncogenic activity of cyclin E still requires functional G1 specific cyclin/CDK complexes. Moreover, inhibition of Myc function also blocks the oncogenic activity of cyclin E indicating a requirement of Myc for cyclin E function. The findings presented here demonstrate that cyclin E can act as an oncoprotein with a potential involvement in genomic instability and the prevention of cell death. Our data also present more evidence for a strict functional interdependency between G1 cyclin/CDK complexes and c-Myc.