Mutant p53 cooperates with the SWI/SNF chromatin remodeling complex to regulate VEGFR2 in breast cancer cells.
Mutant p53 cooperates with the SWI/SNF chromatin remodeling complex to regulate VEGFR2 in breast cancer cells.
复制标题
DOI：
10.1101/gad.263202.115
复制
发表时间：
2015-06-15
影响因子：
10.5
通讯作者：
Prives C
中科院分区：
文献类型：
--
作者：
Pfister NT;Fomin V;Regunath K;Zhou JY;Zhou W;Silwal-Pandit L;Freed-Pastor WA;Laptenko O;Neo SP;Bargonetti J;Hoque M;Tian B;Gunaratne J;Engebraaten O;Manley JL;Børresen-Dale AL;Neilsen PM;Prives C
在这项研究中，Pfister等人鉴定了一种新的突变型p53靶基因VEGFR 2，并证明突变型p53通过与SWI/SNF染色质重塑复合物协同超激活VEGFR 2基因来刺激VEGFR 2的表达。他们还表明，>50%的突变型p53调控的基因表达是由SWI/SNF介导的，这为观察突变型p53改变许多基因的表达提供了见解。突变型p53在转录水平影响许多基因的表达以介导肿瘤发生。我们确定了血管内皮生长因子受体2（VEGFR 2），主要功能的VEGF受体介导的内皮细胞血管化，作为一个突变的p53转录靶在多种乳腺癌细胞系。VEGFR 2的上调介导突变型p53在二维（2D）和三维（3D）培养条件下增加细胞生长的作用。突变型p53在VEGFR 2启动子转录起始位点附近结合，并在维持该位置的开放构象中发挥作用。相关地，突变型p53与SWI/SNF复合物相互作用，这是重塑VEGFR 2启动子所需的。通过查询受突变型p53调控的单个基因并进行RNA测序，结果表明>40%的所有突变型p53调控的基因表达由SWI/SNF介导。我们推测突变型p53通过与SWI/SNF染色质重塑复合物的相互作用和可能的调节，通过启动子重塑影响VEGFR 2以及无数其他基因的转录。因此，不仅突变型p53表达肿瘤可能对抗VEGF治疗敏感，影响突变型p53肿瘤中SWI/SNF肿瘤抑制功能也可能具有治疗潜力。
In this study, Pfister et al. identified a new mutant p53 target gene, VEGFR2, and demonstrated that mutant p53 stimulates expression of VEGFR2 by cooperating with the SWI/SNF chromatin remodeling complex to superactivate the VEGFR2 gene. They also show that >50% of all mutant p53-regulated gene expression is mediated by SWI/SNF, providing insight into the observation that mutant p53 alters the expression of many genes. Mutant p53 impacts the expression of numerous genes at the level of transcription to mediate oncogenesis. We identified vascular endothelial growth factor receptor 2 (VEGFR2), the primary functional VEGF receptor that mediates endothelial cell vascularization, as a mutant p53 transcriptional target in multiple breast cancer cell lines. Up-regulation of VEGFR2 mediates the role of mutant p53 in increasing cellular growth in two-dimensional (2D) and three-dimensional (3D) culture conditions. Mutant p53 binds near the VEGFR2 promoter transcriptional start site and plays a role in maintaining an open conformation at that location. Relatedly, mutant p53 interacts with the SWI/SNF complex, which is required for remodeling the VEGFR2 promoter. By both querying individual genes regulated by mutant p53 and performing RNA sequencing, the results indicate that >40% of all mutant p53-regulated gene expression is mediated by SWI/SNF. We surmise that mutant p53 impacts transcription of VEGFR2 as well as myriad other genes by promoter remodeling through interaction with and likely regulation of the SWI/SNF chromatin remodeling complex. Therefore, not only might mutant p53-expressing tumors be susceptible to anti VEGF therapies, impacting SWI/SNF tumor suppressor function in mutant p53 tumors may also have therapeutic potential.
登录
查看更多内容
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
哺乳动物SWI/SNF复合物的蛋白质组学和生物信息学分析确定了在人类恶性肿瘤中的广泛作用。
影响因子：
30.8
作者：
Kadoch, Cigall;Hargreaves, Diana C.;Hodges, Courtney;Elias, Laura;Ho, Lena;Ranish, Jeff;Crabtree, Gerald R.
通讯作者：
Crabtree, Gerald R.
影响因子：
4.8
作者：
Debnath, J;Muthuswamy, SK;Brugge, JS
通讯作者：
Brugge, JS
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
4.5
作者：
Bruns, Alexander F.;Herbert, Shane P.;Ponnambalam, Sreenivasan
通讯作者：
Ponnambalam, Sreenivasan