The transcription factors Myc and p53 associated with oncogenesis play determinant roles in a human genetic disorder, autosomal dominant polycystic kidney disease (ADPKD), that was coined early in ADPKD etiology a «neoplasia in disguise ». These factors are interdependent master cell regulators of major biological processes including proliferation, apoptosis, cell growth, metabolism, inflammation, fibrosis and differentiation that are all modulated in ADPKD. Myc and p53 proteins evolved to respond and carry out overlapping functions via opposing mechanisms of action. Studies in human ADPKD kidneys, caused by mutations in the PKD1 or PKD2 genes, reveal reduced p53 expression and high expression of Myc in the cystic tubular epithelium. Myc and p53 via direct interaction act respectively, as transcriptional activator and repressor of PKD1 gene expression, consistent with increased renal PKD1 levels in ADPKD. Mouse models generated by Pkd1 and Pkd2 gene dosage dysregulation reproduce renal cystogenesis with activation of Myc expression and numerous signaling pathways, strikingly similar to those determined in human ADPKD. In fact, upregulation of renal Myc expression is also detected in virtually all non-orthologous animal models of PKD. A definitive causal connection of Myc with cystogenesis was established by renal overexpression of Myc in transgenic mice that phenocopies human ADPKD. The network of activated signaling pathways in human and mouse cystogenesis individually or in combination can target Myc as a central node of PKD pathogenesis. One or many of the multiple functions of Myc upon activation can play a role in every phases of ADPKD development and lend credence to the notion of "Myc addiction" for cystogenesis. We propose that the residual p53 levels are conducive to an ADPKD biological program without cancerogenesis while a "p53 dependent annihilation" mechanism would be permissive to oncogenesis. Of major importance, Myc ablation in orthologous mouse models or direct inhibition in non-orthologous mouse model significantly delays cystogenesis consistent with pharmacologic or genetic inhibition of Myc upstream regulator or downstream targets in the mouse. Together, these studies on PKD proteins upon dysregulation not only converged on Myc as a focal point but also attribute to Myc upregulation a causal and « driver » role in pathogenesis. This review will present and discuss our current knowledge on Myc and p53, focused on PKD mouse models and ADPKD.

中文翻译：

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主要调节器 Myc 和 p53 细胞信号传导和在多囊肾病中的功能。

与肿瘤发生相关的转录因子 Myc 和 p53 在人类遗传疾病常染色体显性多囊肾病 (ADPKD) 中起决定性作用，这种疾病在 ADPKD 病因学早期被创造为“变相的瘤形成”。这些因子是主要生物过程的相互依赖的主细胞调节剂，包括增殖、凋亡、细胞生长、代谢、炎症、纤维化和分化，这些都在 ADPKD 中受到调节。Myc 和 p53 蛋白进化为通过相反的作用机制做出反应并执行重叠功能。对由 PKD1 或 PKD2 基因突变引起的人类 ADPKD 肾脏的研究揭示了囊性肾小管上皮中 p53 表达降低和 Myc 高表达。Myc 和 p53 分别通过直接相互作用起作用，作为 PKD1 基因表达的转录激活剂和抑制剂，与 ADPKD 中肾脏 PKD1 水平升高一致。由 Pkd1 和 Pkd2 基因剂量失调生成的小鼠模型通过激活 Myc 表达和众多信号通路重现肾囊肿，与人类 ADPKD 中确定的那些非常相似。事实上，在几乎所有非直系同源的 PKD 动物模型中也检测到肾脏 Myc 表达的上调。Myc 与膀胱发生的明确因果关系是通过 Myc 在表型复制人类 ADPKD 的转基因小鼠中的肾脏过度表达而建立的。人和小鼠膀胱发生中单独或组合的激活信号通路网络可以将 Myc 作为 PKD 发病机制的中心节点。激活后 Myc 的多种功能中的一种或多种功能可以在 ADPKD 发展的每个阶段发挥作用，并为囊形成的“Myc 成瘾”概念提供了可信度。我们建议残留的 p53 水平有利于 ADPKD 生物程序，而不会发生癌变，而“p53 依赖性湮灭”机制将允许肿瘤发生。最重要的是，直系同源小鼠模型中的 Myc 消融或非直系同源小鼠模型中的直接抑制显着延迟了囊肿发生，这与小鼠中 Myc 上游调节器或下游靶标的药理学或遗传抑制一致。总之，这些关于失调时 PKD 蛋白的研究不仅集中在 Myc 作为焦点，而且将 Myc 上调归因于发病机制中的因果和“驱动”作用。