Functional analysis of PI3K/PTEN pathway, a lipid mediator, in vivo
| Project/Area Number |
16390088
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | Akita University |
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Principal Investigator |
SUZUKI Akira Akita University, School of Medicine, Professor, 医学部, 教授 (10311565)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥14,900,000 (Direct Cost: ¥14,900,000)
Fiscal Year 2005: ¥7,200,000 (Direct Cost: ¥7,200,000)
Fiscal Year 2004: ¥7,700,000 (Direct Cost: ¥7,700,000)
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| Keywords | 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 |
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| Research Abstract |
(l)PTEN in hepatocytes
We 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 cells
We 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 prostate
We 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 muscle
We 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
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Report
(3 results)
Research Products
(61 results)
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[Journal Article] Hepatocic gene expression in hepatocyte-specific Pten deficient mice showing steatohepatitis without ethanol challenge.2006
Author(s)
Sato W, Horie Y, Kataoka E, Ohshima S, Dohmen T, Iizuka M, Sasaki J, Sasaki T, Hamada K, Kishimoto H, Suzuki A, Watanabe S
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Journal Title
HEPATOLOGY RESEARCH (in press)
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis.2005
Author(s)
Hamada K, Sasaki T, Koni PA, Natsui M, Kishimoto H, Sasaki J, Yajima N, Hasegawa G, Miyazaki J, Suda T, Itoh H, Nakao K, Mak TW, Nakano T, Suzuki A
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Journal Title
GENES AND DEVELOPMENT 19(17)
Pages: 2054-2065
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Regulation of anaphylactic responses by phosphatidylinositol phosphate kinase type I alpha.2005
Author(s)
Sasaki J, Sasaki T, Yamazaki M, Matsuoka K, Taya C, Shitara H, Takasuga S, Nishio M, Mizuno K, Wada T, Miyazaki H, Watanabe H, Iizuka R, Kubo S, Murata S, Chiba T, Maehama T, Hamada K, Kishimoto H, Frohman MA, Tanaka K, Penninger JM, Yonekawa H, Suzuki A, Kanaho Y
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Journal Title
JOURNAL OF EXPERIMENTAL MEDICINE 201(6)
Pages: 859-870
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Muscle-specific Pten deletion protects against insulin resistance and diabetes.2005
Author(s)
Wijesekara N, Konrad D, Edeida M, Jefferies C, Liadis N, Giacca A, Crockower M, Suzuki A, Mak TW, Kahn CR, Klip A, Woo M
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Journal Title
MOLECULAR AND CELLULAR BIOLOGY 25(3)
Pages: 1135-1145
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinoma2004
Author(s)
Horie Y, Suzuki A (equal first and corresponding author), Kataoka Ei, Sasaki T, Hamada K, Junko Sasaki, Mizuno K, Hasegawa G, Kishimoto H, Iizuka M, Naito M, Enomoto K, Watanabe S, Mak TW, Nakano T
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Journal Title
JOURNAL OF CLINICAL INVESTIGATION 113(12)
Pages: 1774-1783
NAID
Description
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[Journal Article] Early onset of neoplasia in the prostate and skin of mice with tissue-specific deletion of Pten.2004
Author(s)
Backman SA, Ghazarian D, So K, Sanchez O, Wagner KU, Hennighausen L, Suzuki A, Tsao MS, Chapman WB, Stambolic V, Mak TW
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Journal Title
PROC NATL ACAD SCI USA. 101(6)
Pages: 1725-1730
Description
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[Book] 炎症とアポトーシス2004
Author(s)
堀江泰夫ほか
Total Pages
373
Publisher
21世紀の胃の炎症学(メディカルレビュー社)
Description
「研究成果報告書概要(和文)」より
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