Alternations of the Transcriptional Co-activator p300 in Oral Cancers and Its Novel Role in Tumor Suppression

P300乙酰转移酶和转录共激活因子在调节细胞增殖和分化中起着关键作用。P300是病毒癌蛋白的靶标，据报道，在某些类型的癌症中，p300的突变伴随着第二个等位基因的失活。然而，p300/CBP在人类肿瘤发生中的作用仍然不清楚。在这项研究中，我们在两个人类癌细胞系中发现了与第二等位基因失活相关的p300突变。首先，我们在SIHA宫颈癌细胞系中发现了外显子15-18的纯合子p300缺失，这导致了框内缺失，导致了溴化血红蛋白的特异性丢失，这是一个与HAT活性调节有关的保守结构域(Ohshima等人)。2001)。此外，我们在人类口腔鳞状细胞癌HOC313中发现了两个点突变：一个是E1a结合区的错义突变，另一个是导致…的无义突变更多的是C末端富Q和SRC/p160结合结构域的丢失(Suganuma等人)。接下来，我们研究了p300O抑制缺乏正常对应物的细胞生长的能力，以及p300突变对细胞生长控制和转录调控的影响。我们证明，重新导入野生型p300抑制了缺乏正常p300的人类癌细胞的生长，并且肿瘤来源的突变体失去了抑制活性。此外，在p300缺陷的细胞中，对转化生长因子β信号的反应严重受损，而野生型表达恢复了反应(Suganuma等人)。已呈交)。我们还表明，p300的多种不同功能对其染色质重塑和共激活活性非常重要，在抑制肿瘤细胞生长和参与细胞生长负调控的转录调控中发挥关键作用。这些结果首次提供了p30O作为癌细胞生长抑制因子的实验证据，并阐明了p30O在上皮性恶性肿瘤中的作用。较少

The p300 acetyltransferase and transcriptional coactivator plays key roles in the regulation of cell proliferation and differentiation. p300 is targeted by viral oncoproteins, and mutations of p300, accompanied by inactivation of the second allele, have been reported in certain types of cancers, carcinomas. Nevertheless, a role for p300/CBP in human tumorigenesis is still remains poorly understood.In this study, We have identified p300 mutations associated with the inactivation of the second allele in two lines of human carcinoma cells. First, we identified a homozygous p300 deletion of exons 15-18 in the SiHa cervical carcinoma cell line, which results in an in-frame deletion that causes specific loss of the bromodomaimt, a conserved domain implicated in the regulation of HAT activity (Ohshima et al. 2001). In addition, we found two point mutations in the human oral squamouse cell carcinoma HOC313 ; a missence mutation within the E1A binding region, and a nonsense mutation leading to … More a loss of the C-terminal Q-rich and SRC/p160 binding domains (Suganuma et al. submitted).Next, we investigated the ability of p30O to suppress the growth of cells lacking normal counterparts and the effects of p300 mutations on cell growth control and transcriptional regulation. We demonstrate that reintroduction of wild-type p300 suppressed growth of human carcinoma cells lacking normal p300 and the tumor-derived mutants lost suppressive activity. Furthermore, responses to TGFβ signaling, which is important for the negative regulation of epithelial cell growth, were severely impaired in the p300-deficient cells and wild-type expression restored responsiveness (Suganuma et al. submitted). We also show that multiple, distinct functions of p300 important for its chromatin remodeling and coactivator activities play critical roles in both the suppression of tumor cell growth and transcriptional regulation involved in negative regulation of cell growth. These results provide the first experimental evidence that p30O acts as a suppressor of carcinoma cell growth, and shed light on a role for p30O in epithelial malignancies. Less