Alternations of Transcriptional Regulation in Oral Cancers and Analysis of Tumor Suppressive functions of p300 Transcriptional Co-activator

p300乙酰转移酶/转录辅激活因子在细胞增殖和分化的调节中起关键作用。尽管p300是人类癌症突变的靶点，但p300 ICBP在肿瘤发生中的作用仍然知之甚少。在这项研究中，我们在两种人癌细胞系中鉴定了p300（Ohshima et al. 2001，Suganuma et al. 2003）。我们已经证明，野生型p300的重新引入抑制了缺乏正常p300的人癌细胞的生长，并且p300在TGF β 3信号通路中起重要作用，TGF β 3信号通路对于上皮细胞生长的负调节是重要的（Suganuma等，2003）。为了进一步阐明口腔癌的肿瘤发生机制，我们研究了RB肿瘤抑制蛋白的调节以及染色质DNA和核基质之间的相互作用。我们得到了一些观察结果。(1)细胞周期蛋白D1的胞质螯合对RB磷酸化至关重要，分别对终末分化的心肌细胞和神经元的细胞周期退出和存活起重要作用（Tamamori-Adachi et al. 2003）。(2)核基质结合蛋白E2 FBP 1/DRIL 1受p53肿瘤抑制因子调节（Ma et al. 2003）。(3)转录调节复合物向染色质DNA的独特募集介导了E2 F靶基因的激活和抑制，这是由RB家族蛋白调节的（Araki et al. 2003）。

The p300 acetyltransferase/transcriptional coactivator plays key roles in the regulation of cell proliferation and differentiation. Although p300 is targeted for mutations in human carcinomas, a role for p300ICBP in tumorigenesis is still remains poorly understood. In this study, we have identified p300 in two lines of human carcinoma cells (Ohshima et al. 2001, Suganuma et al. 2003). We have demonstrated that reintroduction of wild-type p300 suppressed growth of human carcinoma cells lacking normal p300, and that p300 plays an important role in the TGFJ3 signaling pathway, which is important for the negative regulation of epithelial cell growth (Suganuma et al. 2003).To further elucidate mechanisms of tumorigenesis of oral carcinomas, we have investigated regulation of the RB tumor suppressor protein and the interaction between chromatin DNA and nuclear matrix. We have obtained several observations. (1) Cytoplasinic sequestration of cyclin D1, which is critical for RB phosphorylation, plays an important role for cell cycle exit and survival of terminally differentiated cardiomyocytes and neurons, respectively (Tamamori-Adachi et al. 2003ÅASumrejkanchanakij et al. 2003). (2) The nuclear-matrix-binding protein E2FBP1/DRIL1 is regulated by the p53 tumor suppressor (Ma et al. 2003). (3) Distinct recruitment of transcription regulatory complexes to chromatin DNA mediates activation and repression of an E2F target gene, which is regulated by the RB family proteins (Araki et al. 2003).