Functional analysis of PI3K/PTEN pathway, a lipid mediator, in vivo

脂质介质 PI3K/PTEN 通路的体内功能分析

• 批准号: 16390088
• 负责人: SUZUKI Akira
• 金额: $ 9.54万
• 依托单位: Akita University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390088/
• 关键词: PTEN; Endothelial cells; Skeletal muscle cells; Prostate; Hepatocytes; Cancer; Angiogenesis; diabetes; 脂質; ホスファターゼ; 血糖; PI3K; 非アルコール性脂肪性肝炎; 肝がん

(l)PTEN in hepatocytesWe generated a hepatocyte-specific null mutation of Pten in mice (AlbCrePtenflox/flox mice). AlbCrePtenflox/flox mice showed massive hepatomegaly and steatohepatitis with triglyceride accumulation, a phenotype similar to human nonalcoholic steatohepatitis. Genes involved in lipogenesis and -oxidation were induced, possibly as a result of elevated levels of the transactivating factors PPAR_and SREBP1c. Importantly, the loss of Pten function in the liver led to tumorigenesis, with 47% of AlbCrePtenflox/flox livers developing liver cell adenomas by 44 weeks of age. By 74-78 weeks of age, 100% of AlbCrePtenflox/flox livers showed adenomas and 66% had hepatocellular carcinomas.(2)PTEN in endothelial cellsWe generated an endothelial cell-specific mutation of Pten (Tie2CrePten) in mice. Tie2CrePtenflox/+ mice displayed enhanced tumorigenesis due to an increase in angiogenesis driven by vascular growth factors. Tie2CrePtenflox/flox mice died before embryonic day 11.5 (E11 … More .5) due to bleeding and cardiac failure caused by impaired recruitment of pericytes and vascular smooth muscle cells to blood vessels, and of cardiomyocytes to the endocardium. These phenotypes were associated with decreased expression of Ang-1, VCAM-1, connexin 40, and ephrinB2 but increased expression of Ang-2, VEGF-A, VEGFR1, and VEGFR2.(3)PTEN in prostateWe selectively inactivated Pten in murine tissues in which the MMTV-LTR promoter is active, resulting in hyperproliferation and neoplastic changes in Pten-null skin and prostate. These phenotypes had early onset and were completely penetrant. Abnormalities in Pten mutant prostates from these mice exhibited high-grade prostatic intraepithelial neoplasia (HGPIN) that frequently progressed to focally invasive cancer.(4)PTEN in skeletal muscleWe show that muscle-specific deletion of Pten protected mice from insulin resistance and diabetes caused by high-fat feeding. Deletion of muscle Pten resulted in enhanced insulin-stimulated 2-deoxyglucose uptake and Akt phosphorylation compared to littermate controls upon high-fat feeding, and these mice were spared from developing hyperinsulinemia and islet hyperplasia. Less

(l)肝细胞中的PTEN我们在小鼠（AlbCrePtenflox/flox小鼠）中产生了PTEN的肝细胞特异性零突变。alcreptenflox /flox小鼠表现出大量肝脏肥大和甘油三酯积累的脂肪性肝炎，表型类似于人类非酒精性脂肪性肝炎。参与脂肪生成和氧化的基因被诱导，可能是由于反激活因子ppar_和SREBP1c水平升高的结果。重要的是，肝脏中Pten功能的丧失导致肿瘤发生，47%的AlbCrePtenflox/flox肝脏在44周龄时发展为肝细胞腺瘤。74-78周龄时，100%的alcreptenflox /flox小鼠肝脏显示腺瘤，66%为肝细胞癌。(2)内皮细胞中的PTEN我们在小鼠中产生了内皮细胞特异性的PTEN突变（Tie2CrePten）。Tie2CrePtenflox/+小鼠由于血管生长因子驱动的血管生成增加而表现出增强的肿瘤发生。Tie2CrePtenflox/flox小鼠在胚胎期11.5天前死亡（E11…更多）。5)由于周细胞和血管平滑肌细胞向血管和心肌细胞向心内膜的募集受损而引起的出血和心力衰竭。这些表型与Ang-1、VCAM-1、连接蛋白40和ephrinB2的表达减少有关，而Ang-2、VEGF-A、VEGFR1和VEGFR2的表达增加有关。(3)前列腺中的PTEN我们选择性地灭活小鼠组织中MMTV-LTR启动子活跃的PTEN，导致PTEN缺失的皮肤和前列腺增生和肿瘤改变。这些表型早发且完全具有渗透性。来自这些小鼠的Pten突变前列腺的异常表现为高级别前列腺上皮内瘤变（HGPIN），经常进展为局灶性浸润性癌症。(4)骨骼肌中的PTEN我们发现，肌肉特异性的PTEN缺失可以保护小鼠免受高脂肪喂养引起的胰岛素抵抗和糖尿病。与对照组相比，高脂肪喂养后，肌肉Pten缺失导致胰岛素刺激的2-脱氧葡萄糖摄取和Akt磷酸化增强，这些小鼠没有出现高胰岛素血症和胰岛增生。少

项目成果

Nonalcoholic Steatohepatitis(NASH)への実験医学的アプローチ

非酒精性脂肪性肝炎 (NASH) 的实验医学方法

• 发表时间: 2004
• 期刊: 肝臓 45(11)
• 作者: 渡辺純夫;堀江泰夫;鈴木 聡
• 通讯作者: 鈴木 聡

生活習慣と肝臓病:診断と治療の進歩〜非アルコール性脂肪'性肝炎〜NASHの病態解明(実験モデルからのレッスン)

生活方式习惯与肝脏疾病：诊断和治疗进展 - 非酒精性脂肪性肝炎 - NASH 病理学的阐明（实验模型的教训）

• 发表时间: 2006
• 期刊: 日本内科学雑誌 95(1)
• 作者: Torigoe;H.;Kozasa;T.;Takamori;A.;Ono;A.;堀江泰夫ら
• 通讯作者: 堀江泰夫ら

非アルコール性脂肪性肝炎(NASH)とPTEN遺伝子

非酒精性脂肪性肝炎 (NASH) 和 PTEN 基因

• 发表时间: 2005
• 期刊: 日本臨床 63(8)
• 作者: Ogiwara;H.;Enomoto;T.;Seki;M;佐々木雄彦ら;佐藤亘ら
• 通讯作者: 佐藤亘ら

The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis

• DOI: 10.1101/gad.1308805
• 发表时间: 2005-09-01
• 期刊: GENES & DEVELOPMENT
• 影响因子: 10.5
• 作者: Hamada, K;Sasaki, T;Suzuki, A
• 通讯作者: Suzuki, A

Functional analysis of the tumor suppressor gene PTEN in murine B cells and keratinocytes.

小鼠 B 细胞和角质形成细胞中抑癌基因 PTEN 的功能分析。

• 发表时间: 2004
• 期刊: Biochem.Soc.Trans. 32
• 作者: H.Ijima;T.Takei;K.Kawakami;A.Suzuki
• 通讯作者: A.Suzuki