Loss of Fnip1 alters kidney developmental transcriptional program and synergizes with TSC1 loss to promote mTORC1 activation and renal cyst formation.
Loss of Fnip1 alters kidney developmental transcriptional program and synergizes with TSC1 loss to promote mTORC1 activation and renal cyst formation.
复制标题
DOI：
10.1371/journal.pone.0197973
复制
发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Iritani BM
中科院分区：
文献类型：
--
作者：
Centini R;Tsang M;Iwata T;Park H;Delrow J;Margineantu D;Iritani BM;Gu H;Liggitt HD;Kang J;Kang L;Hockenbery DM;Raftery D;Iritani BM
Birt-Hogg-Dube综合征（BHDS）是一种罕见的人类遗传性疾病，其特征是皮肤错构瘤、肺囊肿、气胸和肾肿瘤风险增加。BHDS是由BHD基因突变引起的，BHD基因编码滤泡蛋白，滤泡蛋白是一种细胞质衔接蛋白，与滤泡蛋白相互作用蛋白-1和-2（Fnip1，Fnip2）以及主能量传感器AMP激酶（AMPK）结合。尽管已知小鼠中Bhd基因的肾特异性缺失会导致多囊肾病（PKD）和肾细胞癌，但Fnip 1在肾细胞发育和功能中的作用尚不清楚。在这项研究中，我们利用Fnip1基因组成性缺失的小鼠来证明Fnip1的缺失足以导致肾囊肿形成，其特征在于AMPK活化降低，mTOR活化增加和代谢过度活化。使用RNAseq，我们发现Fnip1破坏导致了许多先前与人类PKD发展有关的细胞和分子变化，包括离子和氨基酸转运蛋白表达的改变，细胞粘附增加和炎症增加。Fnip1的缺失与Tsc1的缺失协同过度激活mTOR，增加Erk激活，并大大加速PKD的发展。我们的研究结果共同定义了Fnip 1在调节肾脏发育和功能中的作用，并为Fnip 1的缺失如何导致PKD和肾细胞癌提供了模型。
Birt-Hogg-Dube’ Syndrome (BHDS) is a rare genetic disorder in humans characterized by skin hamartomas, lung cysts, pneumothorax, and increased risk of renal tumors. BHDS is caused by mutations in the BHD gene, which encodes for Folliculin, a cytoplasmic adapter protein that binds to Folliculin interacting proteins-1 and -2 (Fnip1, Fnip2) as well as the master energy sensor AMP kinase (AMPK). Whereas kidney-specific deletion of the Bhd gene in mice is known to result in polycystic kidney disease (PKD) and renal cell carcinoma, the roles of Fnip1 in renal cell development and function are unclear. In this study, we utilized mice with constitutive deletion of the Fnip1 gene to show that the loss of Fnip1 is sufficient to result in renal cyst formation, which was characterized by decreased AMPK activation, increased mTOR activation, and metabolic hyperactivation. Using RNAseq, we found that Fnip1 disruption resulted in many cellular and molecular changes previously implicated in the development of PKD in humans, including alterations in the expression of ion and amino acid transporters, increased cell adhesion, and increased inflammation. Loss of Fnip1 synergized with Tsc1 loss to hyperactivate mTOR, increase Erk activation, and greatly accelerate the development of PKD. Our results collectively define roles for Fnip1 in regulating kidney development and function, and provide a model for how loss of Fnip1 contributes to PKD and perhaps renal cell carcinoma.
登录
查看更多内容
DOI：
10.1042/bj20091372
发表时间：
2010-01-27
期刊：
The Biochemical journal
影响因子：
--
作者：
Fogarty S;Hawley SA;Green KA;Saner N;Mustard KJ;Hardie DG
通讯作者：
Hardie DG
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
滤泡素通过调节自噬有助于肾癌中 VHL 肿瘤抑制活性。
影响因子：
3.7
作者：
Bastola P;Stratton Y;Kellner E;Mikhaylova O;Yi Y;Sartor MA;Medvedovic M;Biesiada J;Meller J;Czyzyk-Krzeska MF
通讯作者：
Czyzyk-Krzeska MF
影响因子：
15.9
作者：
Hallows, KR;Raghuram, V;Foskett, JK
通讯作者：
Foskett, JK
影响因子：
4.8
作者：
Hallows, KR;McCane, JE;Foskett, JK
通讯作者：
Foskett, JK