Kunisaki Reiko, Ikawa Shuntaro, Maeda Toyoki, Nakazaki Yukoh, Kurita Ryo, Harata Masamitsu, Shutoh Yukinobu, Bai Yuang Sung, Soda Yasushi, Tanabe Tsuyoshi, Dohi Taeko, Kato Rie, Ikawa Yoji, Asano Shigetaka, Tani Kenzaburo
Division of Molecular Therapy, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
J Gene Med. 2006 Sep;8(9):1121-30. doi: 10.1002/jgm.945.
p51 (p73L/p63/p40/KET), a recently isolated novel p53 homologue, binds to p53-responsive elements to upregulate some p53 target genes and has been suggested to share partially overlapping functions with p53. p51 may be a promising candidate target molecule for anti-cancer therapy.
In this study, we adenovirally transduced p51A cDNA into human lung, gastric and pancreatic cancer cells and analyzed the intracellular function of p51 in anti-oncogenesis in vitro and in vivo.
Overexpression of p51A revealed an anti-proliferative effect in vitro in all the cancer cells examined in this study. The anchorage-dependent and -independent cell growth of EBC1 cells carrying mutations in both p51 and p53 was suppressed and significant apoptosis following adenoviral transduction with p51 and/or p53 was seen. This growth suppression was cooperatively enhanced by the combined infection with adenoviral vectors encoding both p51 and p53. Furthermore, p51 activated several, but not all, p53-inducible genes, indicating that the mechanisms controlling p51- and p53-mediated tumor suppression differed.
Our observations indicate that, although p51 exhibited reduced anti-oncogenetic effects compared with p53, it cooperatively enhanced the anti-tumor effects of p53. Our results suggest that p51 functions as a tumor suppressor in human cancer cells in vitro and in vivo and may be useful as a potential tool for cancer gene therapy.
p51（p73L/p63/p40/KET）是最近分离出的一种新型p53同源物，它与p53反应元件结合以上调一些p53靶基因，并且有人提出它与p53具有部分重叠的功能。p51可能是抗癌治疗中一个有前景的候选靶分子。
在本研究中，我们通过腺病毒将p51A cDNA转导至人肺癌、胃癌和胰腺癌细胞中，并分析了p51在体外和体内抗肿瘤发生中的细胞内功能。
p51A的过表达在本研究检测的所有癌细胞中均显示出体外抗增殖作用。携带p51和p53双突变的EBC1细胞的贴壁依赖性和非贴壁依赖性细胞生长受到抑制，在用p51和/或p53进行腺病毒转导后可见明显的凋亡。用编码p51和p53的腺病毒载体联合感染可协同增强这种生长抑制作用。此外，p51激活了几个但不是所有的p53诱导基因，这表明控制p51和p53介导的肿瘤抑制的机制不同。
我们的观察结果表明，尽管与p53相比，p51的抗肿瘤发生作用有所降低，但它协同增强了p53的抗肿瘤作用。我们的结果表明，p51在体外和体内的人癌细胞中发挥肿瘤抑制作用，可能是癌症基因治疗的一种潜在有用工具。
