科研之友
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摘要
A total of two major isoforms, cyclin Dla and cyclin Dlb, are generated from the human cyclin Dl gene by alternative splicing. Cyclin Dlb is scarcely expressed in normal tissues; however, it is expressed at a high frequency in certain types of cancerous tissue. The present authors previously constructed cyclin Dlb transgenic (Tg) mice and identified rectal tumors, including adenocarcinoma and sessile serrated adenoma, in 62.5% of female Tg mice. In addition, the present authors indicated that cyclin Dlb expression enhances phosphorylation of extracellular signal -regulated kinase (Erk) in these rectal tumors, and in mouse embryonic fibroblast (MEF) cells and human 293T cells. In the present study, it was initially demonstrated that cyclin Dlb has the ability to enhance cell invasiveness by itself; it additionally increases cell invasiveness, anchorage -independent growth and tumorigenicity in cooperation with an activated K-ras oncogene in MEF cells. Phosphorylation of Akt was increased in cyclin Dlb-expressing MEF cells and in the rectal tumor tissues of cyclin Dlb Tg mice. Phosphorylation of Akt was also enhanced by transfection of cyclin Dlb, but not cyclin Dla, in human 293T cells: Treatment with an Akt inhibitor suppressed phosphorylation of Erk in 293T cells expressing cyclin Dlb and D1bTgRT cells established from rectal cancer of the cyclin Dlb Tg mouse. Furthermore, the Akt inhibitor suppressed the invasiveness of D1bTgRT cells and the tumor growth of these cells in nude mice when the Akt inhibitor was injected into the tumors. These results indicate that cyclin Dlb activates Erk through Akt, and that activation of Akt contributes to the tumorigenicity of the cyclin Dlb Tg mice. Inhibitors targeting the phosphoinositide 3-kinase/Akt signaling pathway are thus expected to have therapeutic potential in a variety of human cancer types expressing cyclin Dlb.
- 出版日期2016-12
