Basic Research of Gene Therapy for Glioblastoma by the Tranfer of p16INK4a suppressor gene

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(1) Cell cycle arrested in G0-G1 phase by exogenous expression of p16INK4a into human glioblastoma. The expression of p16INK4a was associated with a decrease in telomerase activity. (2) Cells which expressed p16 protein became a large and flat shape, and the cellular responses such as the phosphorylation of ERK proteins and the expression of c-fos by EGF (epidermal growth factor) stimulation significantly reduced. This results suggest that p16 protein play an important role not only in cell cycle regulation, but also in inducing various cell characteristics such as morphologogical changes, cellular responses by extracellular signals, and actin-cytoskeletal organization. (3) Sodium butyrate inhibited G1-S transition of cell cycle and reduced cell proliferation. This growth suppression was associated with the increased level of p21 protein. Sodium butyrate also inhibited cell invasion on the extracellular matrix proteins. The result suggests that sodium butyrate may be promising compound for glioma therapy. (4) Alternative spliced forms of cyclin D1 (form (a) and (b)) modulate entry in the cell cycle in an inverse manner. (5) Overexpression of cyclin D1 induces glioma invasion by increasing matrix metalloproteinase activity and cell motility,