TFEB and TFE3 drive kidney cystogenesis and tumorigenesis.
TFEB and TFE3 drive kidney cystogenesis and tumorigenesis.
复制标题
DOI：
10.15252/emmm.202216877
复制
发表时间：
2023-05-08
影响因子：
11.1
通讯作者：
Ballabio, Andrea
中科院分区：
文献类型：
--
作者：
Di Malta, Chiara;Zampelli, Angela;Granieri, Letizia;Vilardo, Claudia;De Cegli, Rossella;Cinque, Laura;Nusco, Edoardo;Pece, Salvatore;Tosoni, Daniela;Sanguedolce, Francesca;Sorrentino, Nicolina Cristina;Merino, Maria J.;Nielsen, Deborah;Srinivasan, Ramaprasad;Ball, Mark W.;Ricketts, Christopher J.;Vocke, Cathy D.;Lang, Martin;Karim, Baktiar;Lanfrancone, Luisa;Schmidt, Laura S.;Linehan, W. Marston;Ballabio, Andrea
Birt-Hogg-Dubé（BHD）综合征是一种遗传性家族性癌症综合征，其特征为发生皮肤病变、肺囊肿、肾肿瘤和囊肿，由编码肿瘤抑制蛋白卵泡素（FLCN）的基因中的功能丧失致病性变体引起。FLCN作为TFEB和TFE 3转录因子的负调节因子，溶酶体生物发生和自噬的主控制器，通过使它们被雷帕霉素复合物1（mTORC 1）的机制靶标磷酸化。我们之前已经表明，Tfeb的缺失挽救了肾特异性Flcn KO小鼠的肾囊肿表型。使用Flcn/Tfeb/Tfe 3双和三重KO小鼠，我们现在表明，Tfeb和Tfe 3的贡献，在一个差异和合作的方式，肾脏囊肿。值得注意的是，对BHD患者来源的肿瘤样本的分析显示，TFEB/TFE 3介导的转录程序的激活增加，并且两种基因中的任一种沉默在人BHD肾肿瘤细胞系来源的异种移植物（CDX）中挽救了肿瘤发生。我们的研究结果表明，在疾病相关模型中，TFEB和TFE 3都是肾肿瘤发生的关键驱动因素，并提出了基于抑制这些转录因子的新治疗策略。TFEB和TFE 3转录因子是细胞代谢的主要调节因子。这项研究表明，在Birt-Hogg-Dubé（BHD）遗传性癌症综合征中，这些因子同时激活细胞分解代谢和合成代谢途径，在肾脏囊肿发生和肿瘤发生中发挥关键作用。
Birt‐Hogg‐Dubé (BHD) syndrome is an inherited familial cancer syndrome characterized by the development of cutaneous lesions, pulmonary cysts, renal tumors and cysts and caused by loss‐of‐function pathogenic variants in the gene encoding the tumor‐suppressor protein folliculin (FLCN). FLCN acts as a negative regulator of TFEB and TFE3 transcription factors, master controllers of lysosomal biogenesis and autophagy, by enabling their phosphorylation by the mechanistic Target Of Rapamycin Complex 1 (mTORC1). We have previously shown that deletion of Tfeb rescued the renal cystic phenotype of kidney‐specific Flcn KO mice. Using Flcn/Tfeb/Tfe3 double and triple KO mice, we now show that both Tfeb and Tfe3 contribute, in a differential and cooperative manner, to kidney cystogenesis. Remarkably, the analysis of BHD patient‐derived tumor samples revealed increased activation of TFEB/TFE3‐mediated transcriptional program and silencing either of the two genes rescued tumorigenesis in human BHD renal tumor cell line‐derived xenografts (CDXs). Our findings demonstrate in disease‐relevant models that both TFEB and TFE3 are key drivers of renal tumorigenesis and suggest novel therapeutic strategies based on the inhibition of these transcription factors. TFEB and TFE3 transcription factors are master regulators of cell metabolism. This study shows that in Birt‐Hogg‐Dubé (BHD) hereditary cancer syndrome, these factors concomitantly activate cellular catabolic and anabolic pathways, playing a key role in kidney cystogenesis and tumorigenesis.
登录
查看更多内容
DOI：
10.1074/mcp.m111.011015
发表时间：
2011-09
期刊：
Molecular & cellular proteomics : MCP
影响因子：
--
作者：
Michalski A;Damoc E;Hauschild JP;Lange O;Wieghaus A;Makarov A;Nagaraj N;Cox J;Mann M;Horning S
通讯作者：
Horning S
影响因子：
13.6
作者：
Gambardella G;Staiano L;Moretti MN;De Cegli R;Fagnocchi L;Di Tullio G;Polletti S;Braccia C;Armirotti A;Zippo A;Ballabio A;De Matteis MA;di Bernardo D
通讯作者：
di Bernardo D
影响因子：
5.7
作者：
Furuya M;Hong SB;Tanaka R;Kuroda N;Nagashima Y;Nagahama K;Suyama T;Yao M;Nakatani Y
通讯作者：
Nakatani Y
影响因子：
64.8
作者：
Perera, RushikaM.;Stoykova, Svetlana;Nicolay, Brandon N.;Ross, Kenneth N.;Fitamant, Julien;Boukhali, Myriam;Lengrand, Justine;Deshpande, Vikram;Selig, Martin K.;Ferrone, Cristina R.;Settleman, Jeff;Stephanopoulos, Gregory;Dyson, Nicholas J.;Zoncu, Roberto;Ramaswamy, Sridhar;Haas, Wilhelm;Bardeesy, Nabeel
通讯作者：
Bardeesy, Nabeel
影响因子：
56.9
作者：
Lawrence, Rosalie E.;Fromm, Simon A.;Zoncu, Roberto
通讯作者：
Zoncu, Roberto