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

(1)外源性p16INK4a在人胶质母细胞瘤中的表达将细胞周期阻滞在G0-G1期。p16INK4a的表达与端粒酶活性降低有关。(2)表达p16蛋白的细胞变得大而扁平，EGF（表皮生长因子）刺激下ERK蛋白磷酸化和c-fos表达等细胞反应显著降低。这些结果表明，p16蛋白不仅在细胞周期调节中发挥重要作用，而且在诱导各种细胞特征，如形态学变化、细胞外信号的细胞反应和肌动蛋白-细胞骨架组织等方面发挥重要作用。(3)丁酸钠抑制细胞周期G1-S转变，降低细胞增殖。这种生长抑制与p21蛋白水平升高有关。丁酸钠还能抑制细胞对细胞外基质蛋白的侵袭。结果表明，丁酸钠可能是治疗胶质瘤的有前途的化合物。(4) cyclin D1的可选剪接形式(形式（a)和(b)）以相反的方式调节细胞周期的进入。(5) cyclin D1过表达通过增加基质金属蛋白酶活性和细胞运动诱导胶质瘤侵袭；

(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,