蛋白酶体激活因子PA28γ可变剪接体5在口腔鳞癌异常增殖中的作用、分子机制及结构基础研究

蛋白酶体激活因子PA28γ变体1能介导多种肿瘤相关靶蛋白通过蛋白酶体途径被降解, 并能影响口腔鳞癌的增殖及凋亡。申请人在口腔鳞癌细胞中鉴定了截短型可变剪接体PA28γ变体5，然而其在口腔鳞癌中的作用机理尚未明确。生物信息学分析发现该变体含有PA28家族成员的激活环序列，通过瞬时转染HEK293细胞发现该变体能导致p53显著的下调，这些结果提示我们PA28γ变体5可能发挥蛋白酶体激活因子的作用并影响口腔鳞癌的进展。本课题在前期工作基础上，将以口腔鳞癌细胞为模型，研究PA28γ变体5对口腔鳞癌增殖、凋亡及裸鼠成瘤的影响及其分子机制，并将通过结构生物学相关技术研究PA28γ变体5的蛋白质结构，从而为将该变体作为口腔鳞癌的治疗靶标提供理论依据，同时也为通过小分子抑制剂干预PA28γ变体5治疗口腔鳞癌提供结构基础。

Proteasome activator PA28γcan affect the degradation of cancer-related proteins, as well as the proliferation and apoptosis of the oral squamous cell carcinoma (OSCC). Although proposer identified a truncated PA28γsplicing variant 5 in OSCC , its function is unknown. Bioinformatics analysis and transient transfection to HEK293 cells showed that it keeps the activation motif in PA28 family and results in the down-regulation of p53 respectively, these results suggest that PA28γsplicing variant 5 is likely to play a role in the development of OSCC. This proposal will study on the function、molecular mechanism of PA28γsplicing variant 5 in OSCC and its protein structure. These data will confirm the possibility of regarding PA28γsplicing variant 5 as a treatment target of OSCC. At the same time, it will provide the structure model for development of small molecule compound to bind with PA28γsplicing variant 5.