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首页> 外文期刊>Oncogene >PAX8 promotes tumor cell growth by transcriptionally regulating E2F1 and stabilizing RB protein
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PAX8 promotes tumor cell growth by transcriptionally regulating E2F1 and stabilizing RB protein

机译：PAX8通过转录调节E2F1和稳定RB蛋白来促进肿瘤细胞生长

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The retinoblastoma protein (RB)–E2F1 pathway has a central role in regulating the cell cycle. Several PAX proteins (tissue-specific developmental regulators), including PAX8, interact with the RB protein, and thus regulate the cell cycle directly or indirectly. Here, we report that PAX8 expression is frequent in renal cell carcinoma, bladder, ovarian and thyroid cancer cell lines, and that silencing of PAX8 in cancer cell lines leads to a striking reduction in the expression of E2F1 and its target genes, as well as a proteasome-dependent destabilization of RB protein, with the RB1 mRNA level remaining unaffected. Cancer cells expressing PAX8 undergo a G1/S arrest and eventually senesce following PAX8 silencing. We demonstrate that PAX8 transcriptionally regulates the E2F1 promoter directly, and E2F1 transcription is enhanced after RB depletion. RB is recruited to the PAX8-binding site, and is involved in PAX8-mediated E2F1 transcription in cancer cells. Therefore, our results suggest that, in cancer, frequent and persistent expression of PAX8 is required for cell growth control through transcriptional activation of E2F1 expression and upregulation of the RB–E2F1 pathway.
机译：视网膜母细胞瘤蛋白（RB）–E2F1通路在调节细胞周期中起着核心作用。包括PAX8在内的几种PAX蛋白（组织特异性发育调节剂）与RB蛋白相互作用，从而直接或间接调节细胞周期。在这里，我们报道了PAX8在肾细胞癌，膀胱癌，卵巢癌和甲状腺癌细胞系中的表达频繁，而PAX8在癌细胞系中的沉默导致E2F1及其靶基因以及其表达的显着降低。蛋白酶体依赖性的RB蛋白不稳定，RB1 mRNA水平保持不变。表达PAX8的癌细胞会经历G1 / S停滞，并在PAX8沉默后最终衰老。我们证明PAX8转录直接调节E2F1启动子，并且RB耗尽后E2F1转录增强。 RB被募集到PAX8结合位点，并参与癌细胞中PAX8介导的E2F1转录。因此，我们的结果表明，在癌症中，PAX8的频繁和持续表达是通过E2F1表达的转录激活和RB–E2F1通路的上调控制细胞生长所必需的。

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