Differential regulation of MYC expression by PKHD1/Pkhd1 in human and mouse kidneys: phenotypic implications for recessive polycystic kidney disease.
Differential regulation of MYC expression by PKHD1/Pkhd1 in human and mouse kidneys: phenotypic implications for recessive polycystic kidney disease.
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DOI：
10.3389/fcell.2023.1270980
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发表时间：
2023
影响因子：
5.5
通讯作者：
Guay-Woodford, Lisa M.
中科院分区：
文献类型：
--
作者：
Harafuji, Naoe;Yang, Chaozhe;Wu, Maoqing;Thiruvengadam, Girija;Gordish-Dressman, Heather;Thompson, R. Griffin;Bell, P. Darwin;Rosenberg, Avi Z.;Dafinger, Claudia;Liebau, Max C.;Bebok, Zsuzsanna;Caldovic, Ljubica;Guay-Woodford, Lisa M.
常染色体隐性遗传性多囊肾病(ARPKD；MIM#263200)是一种严重的遗传性肝肾纤维囊性疾病，可导致儿童早期发病率和死亡率。典型的ARPKD是由PKHD1基因的致病变异引起的，PKHD1基因编码纤维囊藻蛋白/多聚管蛋白(FPC)。MYC的过度表达被认为是肾脏囊变的驱动因素，但对MYC在隐性PKD中的表达知之甚少。在目前的研究中，我们首次提供了MYC在ARPKD患者肾脏中过度表达的证据，并证实了MYC在CPK突变小鼠的囊性肾脏中表达上调。相反，在几个缺乏明显囊性肾脏表型的Pkhd1突变小鼠中，肾脏MYC的表达水平没有改变。我们利用先前的观察结果，即小鼠FPC的羧基末端(FPC-CTD)通过Notch-like加工被蛋白质水解性切割，移位到细胞核，并与双链DNA结合，以检测FPC-CTD是否在调节MYC/Myc转录中发挥作用。通过免疫荧光、报告基因分析和芯片检测，我们证实人和小鼠的FPC-CTD都可以定位于细胞核，结合MYC/Myc P1启动子，并激活MYC/Myc的表达。有趣的是，我们观察到了FPC-CTD细胞内转运的物种特异性差异。此外，我们的信息学分析显示，FPC-CTD在脊椎动物门中的序列同源性有限，数据库查询发现PKHD1/Pkhd1和Cys1/Cys1在小鼠和人类肾脏中的表达模式存在时间差异。鉴于Cys1基因产物Cystin是Myc转录的负调控因子，这些基因表达的时间差异可能有助于Pkhd1基因缺陷小鼠的相对肾脏保护，使其免受囊变的影响。综上所述，我们的发现为MFPC-CTD和hFPC-CTD对肾上皮细胞MYC表达的差异提供了新的机制见解，这可能阐明了PKHD1致病变异体患者和Pkhd1突变小鼠之间表型差异的基础。
Autosomal recessive polycystic kidney disease (ARPKD; MIM#263200) is a severe, hereditary, hepato-renal fibrocystic disorder that leads to early childhood morbidity and mortality. Typical forms of ARPKD are caused by pathogenic variants in the PKHD1 gene, which encodes the fibrocystin/polyductin (FPC) protein. MYC overexpression has been proposed as a driver of renal cystogenesis, but little is known about MYC expression in recessive PKD. In the current study, we provide the first evidence that MYC is overexpressed in kidneys from ARPKD patients and confirm that MYC is upregulated in cystic kidneys from cpk mutant mice. In contrast, renal MYC expression levels were not altered in several Pkhd1 mutant mice that lack a significant cystic kidney phenotype. We leveraged previous observations that the carboxy-terminus of mouse FPC (FPC-CTD) is proteolytically cleaved through Notch-like processing, translocates to the nucleus, and binds to double stranded DNA, to examine whether the FPC-CTD plays a role in regulating MYC/Myc transcription. Using immunofluorescence, reporter gene assays, and ChIP, we demonstrate that both human and mouse FPC-CTD can localize to the nucleus, bind to the MYC/Myc P1 promoter, and activate MYC/Myc expression. Interestingly, we observed species-specific differences in FPC-CTD intracellular trafficking. Furthermore, our informatic analyses revealed limited sequence identity of FPC-CTD across vertebrate phyla and database queries identified temporal differences in PKHD1/Pkhd1 and CYS1/Cys1 expression patterns in mouse and human kidneys. Given that cystin, the Cys1 gene product, is a negative regulator of Myc transcription, these temporal differences in gene expression could contribute to the relative renoprotection from cystogenesis in Pkhd1-deficient mice. Taken together, our findings provide new mechanistic insights into differential mFPC-CTD and hFPC-CTD regulation of MYC expression in renal epithelial cells, which may illuminate the basis for the phenotypic disparities between human patients with PKHD1 pathogenic variants and Pkhd1-mutant mice.
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影响因子：
4.8
作者：
Hiesberger, Thomas;Gourley, Eric;Igarashi, Peter
通讯作者：
Igarashi, Peter
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3.7
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Wu M;Yang C;Tao B;Bu S;Guay-Woodford LM
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Guay-Woodford LM
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作者：
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