Kidney-targeted Birt-Hogg-Dube gene inactivation in a mouse model: Erk1/2 and Akt-mTOR activation, cell hyperproliferation, and polycystic kidneys

被引：190

作者：

Baba, Masaya ^{[1
,8
,9
]}

Furihata, Mutsuo ^{[10
]}

Hong, Seung-Beom ^{[1
,8
]}

Tessarollo, Lino ^{[2
]}

Haines, Diana C. ^{[3
]}

Southon, Eileen ^{[4
]}

Patel, Vishal ^{[11
]}

Igarashi, Peter ^{[11
]}

Alvord, W. Gregory ^{[6
,7
]}

Leighty, Robert ^{[6
,7
]}

Yao, Masahiro ^{[12
]}

Bernardo, Marcelino

Ileva, Lilia ^{[5
]}

Choyke, Peter ^{[9
]}

Warren, Michelle B. ^{[1
,8
]}

Zbar, Berton ^{[1
,8
]}

Linehan, W. Marston ^{[1
,8
]}

Schmidt, Laura S. ^{[1
,4
,8
]}

机构：

[1] Natl Canc Inst, Urol Oncol Branch, Ft Detrick, MD 21702 USA

[2] Mouse Canc Genet Program, Frederick, MD USA

[3] Ctr Canc Res, Pathol Histechnol Lab, Frederick, MD USA

[4] Basic Res Program, Frederick, MD USA

[5] Lab Anim Sci Program, Small Anim Imaging Program, Frederick, MD USA

[6] SAIC Frederick Inc, Frederick, MD USA

[7] Data Management Serv Inc, Frederick, MD USA

[8] Natl Inst Hlth, Natl Canc Inst, Ctr Canc Res, Urol Oncol Branch, Bethesda, MD USA

[9] Natl Inst Hlth, Natl Canc Inst, Ctr Canc Res, Mol Imaging Program, Bethesda, MD USA

[10] Kochi Med Sch, Dept Pathol, Kochi, Japan

[11] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA

[12] Yokohama City Univ, Grad Sch Med, Dept Urol & Mol Genet, Yokohama, Kanagawa 232, Japan

来源：

JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE | 2008年 / 100卷 / 02期

关键词：

D O I：

10.1093/jnci/djm288

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background Patients with Birt-Hogg-Dube ( BHD) syndrome harbor germline mutations in the BHD tumor suppressor gene that are associated with an increased risk for kidney cancer. BHD encodes folliculin, a protein that may interact with the energy- and nutrient-sensing 5'-AMP-activated protein kinase-mammalian target of rapamycin (AMPK-mTOR) signaling pathways. Methods We used recombineering methods to generate mice with a conditional BHD allele and introduced the cadherin 16 ( KSP)-Cre transgene to target BHD inactivation to the kidney. Kidney cell proliferation was measured by BrdU incorporation and phospho-histone H3 staining. Kidney weight data were analyzed with Wilcoxon's rank-sum, Student's t, and Welch's t tests. Hematoxylin and eosin staining and immunoblot analysis and immunohistochemistry of cell cycle and signaling proteins were performed on mouse kidney cells and tissues. BHD knockout mice and kidney cells isolated from BHD knockout and control mice were treated with the mTOR inhibitor rapamycin. Mouse survival was evaluated by Kaplan-Meier analyses. All statistical tests were two-sided. Results BHD knockout mice developed enlarged polycystic kidneys and died from renal failure by 3 weeks of age. Targeted BHD knockout led to the activation of Raf-extracellular signal-regulated protein kinase ( Erk)1/ 2 and Akt-mTOR pathways in the kidneys and increased expression of cell cycle proteins and cell proliferation. Rapamycin-treated BHD knockout mice had smaller kidneys than buffer-treated BHD knockout mice had ( n = 4 - 6 mice per group, relative kidney/ body weight ratios, mean = 4.64% vs 12.2%, difference = 7.6%, 95% confidence interval = 5.2% to 10.0%; P <.001) and longer median survival time ( n = 4 - 5 mice per group, 41.5 vs 23 days; P =.0065). Conclusions Homozygous loss of BHD may initiate renal tumorigenesis in the mouse. The conditional BHD knockout mouse may be a useful research model for dissecting multistep kidney carcinogenesis, and rapamycin may be considered as a potential treatment for Birt-Hogg-Dube syndrome.

引用

页码：140 / 154

页数：15

共 43 条

[1] Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling [J].