p53 mutants induce transcription of NF-κB2 in H1299 cells through CBP and STAT binding on the NF-κB2 promoter and gain of function activity.
p53 mutants induce transcription of NF-κB2 in H1299 cells through CBP and STAT binding on the NF-κB2 promoter and gain of function activity.
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DOI：
10.1016/j.abb.2011.12.006
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发表时间：
2012-02-01
影响因子：
3.9
通讯作者：
Deb, Sumitra
中科院分区：
文献类型：
--
作者：
Vaughan, Catherine A.;Singh, Shilpa;Windle, Brad;Sankala, Heidi M.;Graves, Paul R.;Yeudall, W. Andrew;Deb, Swati P.;Deb, Sumitra
一般来说，具有p53突变的癌细胞比具有野生型p53的癌细胞生长更积极，并显示出“功能获得”（GOF）表型，例如生长速率增加，对化疗药物的抗性增强，细胞运动性和致瘤性增加;尽管这种功能的机制仍然未知。在本文中，我们报告了p53介导的NF-κB2上调显着促进了癌细胞的侵袭性致癌行为。在许多癌细胞系中降低突变型p53的水平导致GOF表型的损失，直接涉及p53突变体的过程。在天然存在的癌细胞系中针对NF-κB2的RNAi也降低了GOF活性。在表达突变型p53的H1299细胞中，染色质免疫沉淀（ChIP）试验表明突变型p53在其靶基因调控区的特定位点诱导组蛋白乙酰化。使用能够与NF-κB2启动子相互作用的转录因子p53的抗体进行的ChIP试验显示，在存在突变型p53的情况下，CBP和STAT 2的相互作用增加。因此，我们提出，在H1299细胞中，突变型p53通过在引起CBP介导的组蛋白乙酰化的启动子上募集CBP和STAT 2来诱导组蛋白乙酰化，从而提高能够增强细胞增殖、运动性和致瘤性的基因的表达。
Cancer cells with p53 mutations, in general, grow more aggressively than those with wild-type p53 and show “gain of function”(GOF) phenotypes such as increased growth rate, enhanced resistance to chemotherapeutic drugs, increased cell motility and tumorigenicity; although the mechanism for this function remains unknown. In this communication we report that p53-mediated NF-κB2 up-regulation significantly contributes to the aggressive oncogenic behavior of cancer cells. Lowering the level of mutant p53 in a number of cancer cell lines resulted in a loss of GOF phenotypes directly implicating p53 mutants in the process. RNAi against NF-κB2 in naturally occurring cancer cell lines also lowers GOF activities. In H1299 cells expressing mutant p53, chromatin immunoprecipitation (ChIP) assays indicate that mutant p53 induces histone acetylation at specific sites on the regulatory regions of its target genes. ChIP assays using antibodies against transcription factors putatively capable of interacting with the NF-κB2 promoter show increased interaction of CBP and STAT2 in the presence of mutant p53. Thus, we propose that in H1299 cells, mutant p53 elevates expression of genes capable of enhancing cell proliferation, motility, and tumorigenicity by inducing acetylation of histones via recruitment of CBP and STAT2 on the promoters causing CBP-mediated histone acetylation.
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影响因子：
8
作者：
Bristow, RG;Peacock, J;Benchimol, S
通讯作者：
Benchimol, S
影响因子：
4.8
作者：
Livengood, JA;Scoggin, KES;Nyborg, JK
通讯作者：
Nyborg, JK
影响因子：
8
作者：
Blandino, G;Levine, AJ;Oren, M
通讯作者：
Oren, M
DOI：
10.1073/pnas.90.12.5742
发表时间：
1993-06-15
影响因子：
11.1
作者：
LEE, JM;BERNSTEIN, A
通讯作者：
BERNSTEIN, A
影响因子：
4.8
作者：
Paulson, M;Pisharody, S;Levy, DE
通讯作者：
Levy, DE