Keskin Nazli, Deniz Emre, Eryilmaz Jitka, Un Manolya, Batur Tugce, Ersahin Tulin, Cetin Atalay Rengul, Sakaguchi Shinya, Ellmeier Wilfried, Erman Batu
Biological Sciences and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey Sabanci University Nanotechnology Research and Application Center-SUNUM, Istanbul, Turkey.
Biological Sciences and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey.
Mol Cell Biol. 2015 May;35(10):1741-53. doi: 10.1128/MCB.01475-14. Epub 2015 Mar 9.
Insults to cellular health cause p53 protein accumulation, and loss of p53 function leads to tumorigenesis. Thus, p53 has to be tightly controlled. Here we report that the BTB/POZ domain transcription factor PATZ1 (MAZR), previously known for its transcriptional suppressor functions in T lymphocytes, is a crucial regulator of p53. The novel role of PATZ1 as an inhibitor of the p53 protein marks its gene as a proto-oncogene. PATZ1-deficient cells have reduced proliferative capacity, which we assessed by transcriptome sequencing (RNA-Seq) and real-time cell growth rate analysis. PATZ1 modifies the expression of p53 target genes associated with cell proliferation gene ontology terms. Moreover, PATZ1 regulates several genes involved in cellular adhesion and morphogenesis. Significantly, treatment with the DNA damage-inducing drug doxorubicin results in the loss of the PATZ1 transcription factor as p53 accumulates. We find that PATZ1 binds to p53 and inhibits p53-dependent transcription activation. We examine the mechanism of this functional inhibitory interaction and demonstrate that PATZ1 excludes p53 from DNA binding. This study documents PATZ1 as a novel player in the p53 pathway.
对细胞健康的损害会导致p53蛋白积累，而p53功能的丧失会引发肿瘤发生。因此，p53必须受到严格调控。在此我们报告，BTB/POZ结构域转录因子PATZ1（MAZR），此前因其在T淋巴细胞中的转录抑制功能而为人所知，是p53的关键调节因子。PATZ1作为p53蛋白抑制剂的新作用将其基因标记为原癌基因。PATZ1缺陷细胞的增殖能力降低，我们通过转录组测序（RNA-Seq）和实时细胞生长速率分析对此进行了评估。PATZ1改变了与细胞增殖基因本体术语相关的p53靶基因的表达。此外，PATZ1调节多个参与细胞黏附和形态发生的基因。值得注意的是，用DNA损伤诱导药物阿霉素处理会导致随着p53积累PATZ1转录因子的丧失。我们发现PATZ1与p53结合并抑制p53依赖的转录激活。我们研究了这种功能性抑制相互作用的机制，并证明PATZ1阻止p53与DNA结合。这项研究证明PATZ1是p53通路中的一个新成员。
