Pax2 通过AP-1 促进肿瘤细胞增殖及PHD3 对 Pax2 的调节作用
文献类型：学位论文
| 作者 | 闫冰 |
| 学位类别 | 博士 |
| 答辩日期 | 2011-05 |
| 授予单位 | 中国科学院上海生命科学研究院营养科学研究所 |
| 授予地点 | 中国科学院上海生命科学研究院 |
| 导师 | 方靖 |
| 关键词 | 转录因子Pax2 AP-1 脯氨酸羟基化酶3 肿瘤增殖 |
| 其他题名 | Pax2 promotes cancer cell proliferation via AP-1 pathway and PHD3 binds to Pax2 and targets it for destruction |
| 学位专业 | 生物化学与分子生物学 |
| 中文摘要 | 肿瘤已经日益成为当今公共健康的一大危害，随着分子生物学技术的发展，人们期望找到合适的分子靶标用于肿瘤治疗。Pax2（Paired Box2）是一个转录因子，在胚胎期肾脏，眼，耳等器官发育中发挥重要作用，Pax2的表达水平随着发育的完成而降低。但是，最近研究指出一系列肿瘤中都发生了Pax2的高表达。Pax2的异常表达被认为与肿瘤细胞的恶性增殖相关，但Pax2在肿瘤细胞中如何促进肿瘤细胞增殖以及肿瘤中Pax2的表达调控都有待研究。 本论文分两部分，分别为Pax2促进肿瘤细胞增殖的机制研究和肿瘤细胞中Pax2表达调控的机制研究。我们发现，Pax2在结直肠癌组织中表达也高于正常组织。利用小干扰RNA沉默的方法降低肿瘤细胞中Pax2的表达水平后，肿瘤细胞的增殖速度减慢。进一步研究结果表明，Pax2能够通过AP-1调节CyclinD1的表达水平，促进细胞增殖。鉴于Pax2对肿瘤增殖的重要作用，它自身表达水平的调节就成为我们关心的问题。我们发现，一个脯氨酸羟基化酶家族成员，PHD3，能够调节Pax2的表达。PHD3能够结合Pax2，并且能够促进Pax2的降解。PHD3对Pax2的调节发生在转录后水平，过表达PHD3对Pax2的mRNA水平并没有影响，但能够显著下调其蛋白表达水平。此外，我们发现PHD3失去羟基化酶活性的突变体不能介导Pax2的降解，表明PHD3的羟基化酶活性可能是Pax2降解所必需的。PHD家族的另外两个成员PHD1,2对Pax2没有作用。此外pVHL也能够介导Pax2的降解。pVHL与Pax2的结合需要以Pax2的羟基化为前提。这暗示我们，PHD3/VHL除了介导经典的HIFα分子降解外，亦介导其它分子降解。通过进一步的研究，我们发现结肠癌中PHD3的表达与Pax2的表达呈现负相关，这进一步提示肿瘤细胞中PHD3是Pax2表达一个负调控因子，肿瘤组织中Pax2升高的可能与PHD3的表达下调有关。我们的研究结果表明Pax2是PHD3一个新的靶分子，而Pax2在肿瘤增殖中发挥重要作用，使得Pax2有可能成为肿瘤治疗一个潜在的分子靶标。 |
| 索取号 | D2009-077 |
| 英文摘要 | Cancer is one of the most important public health problems in the world. With the development of molecular biology，people are looking for suitable molecules as the target for cancer therapy. Pax2 (Paired Box2) is a crucial transcriptional factor, acting to play an important role in embryogenesis, including the development of kidney, ear and eye. Normally, the expression of Pax2 is declined when development is complete. However, Pax2 re-expression is observed in a variety of cancers, including renal carcinoma, breast cancer, and prostate cancer. The aberrant expression of Pax2 is associated with cancer cell proliferation. However, the underlying mechanism remains largely unknown. Also, the regulation of expression of Pax2 is poorly understood. We determined the possible mechanism for the regulation of cancer cell proliferation by Pax2. We also investigated the expression profile of Pax2 in human colorectal cancer and the possible mechanisms for the regulation of Pax2 expression in cancer cells. We found that Pax2 was over-expressed in colorectal cancers compared with normal tissues. Pax2 could increase the expression of CyclinD1 and promote cell proliferation. The regulation of CyclinD1 by Pax2 was through AP-1. Pax2 could activate AP-1 transcriptional ability through increasing c-Jun phosphorylation. Also, Pax2 could enhance DNA binding ability of AP-1 through competing with c-Jun for binding to JunB, the blocker of AP-1 pathway. We found that PHD3 bound to Pax2 and mediated Pax2 degradation. And the hydroxylase activity of PHD3 was important in the regulation of Pax2. Inhibition of PHD3 hydroxylase activity increased Pax2 protein but not mRNA level, indicating HIF was not involved directly. pVHL was involved in PHD3-mediated degradation of Pax2. Pax2 protein was increased and PHD3 protein was decreased in colorectal tumors and the up-regulation of Pax2 was correlated with the down-regulation of PHD3. Our results disclose a novel mechanism for the regulation of Pax2 expression in cancer cells. And Pax2 could be a candidate target gene for cancer therapies. |
| 语种 | 中文 |
| 公开日期 | 2015-12-24 |
| 源URL | [http://202.127.25.144/handle/331004/372]  |
| 专题 | 中国科学院上海生命科学研究院营养科学研究所_营养与癌症研究组 |
| 推荐引用方式 GB/T 7714 | 闫冰. Pax2 通过AP-1 促进肿瘤细胞增殖及PHD3 对 Pax2 的调节作用[D]. 中国科学院上海生命科学研究院. 中国科学院上海生命科学研究院营养科学研究所. 2011. |
入库方式： OAI收割
来源：上海营养与健康研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。