EAF2 loss enhances angiogenic effects of Von Hippel-Lindau heterozygosity on the murine liver and prostate

CORC > 水生生物研究所 > 中科院水生所知识产出（2009年前） > 水生生物分子与细胞生物学研究中心 > 期刊论文

	EAF2 loss enhances angiogenic effects of Von Hippel-Lindau heterozygosity on the murine liver and prostate
	Pascal, Laura E.1; Ai, Junkui 1; Rigatti, Lora H.2; Lipton, Anne K.1,4; Xiao, Wuhan 1,3; Gnarra, James R.1; Wang, Zhou 1,4
刊名	ANGIOGENESIS
	2011-09-01
卷号	14 期号:3 页码:331-343
关键词	Von Hippel-Lindau (VHL) ELL-associated factor 2 (EAF2) Hepatic vascular lesion Prostatic intraepithelial neoplasia (PIN)
ISSN号	0969-6970
通讯作者	Wang, Z (reprint author), Univ Pittsburgh, Sch Med, Dept Urol, Suite G40,5200 Ctr Ave, Pittsburgh, PA 15232 USA ; pascalle@upmc.edu ; aij@upmc.edu ; rigattil@pitt.edu ; liptonak@upmc.edu ; w-xiao@ihb.ac.cn ; gnarrajr@upmc.edu ; wangz2@upmc.edu
中文摘要	Von Hippel-Lindau (VHL) disease results from the inactivation of the VHL gene and is characterized by highly vascular tumors. A consequence of VHL loss is the stabilization of hypoxia-inducible factor (HIF) alpha subunits and increased expression of HIF target genes, which include pro-angiogenic growth factors such as vascular endothelial growth factor (VEGF). In mice, homozygous deletion of VHL is embryonic lethal due to vascular abnormalities in the placenta; and, VHL(+/-) mice develop proliferative vascular lesions in several major organs, most prominently the liver. Loss of ELL-associated factor (EAF2) in murine models has also been shown to induce increased vascular density in the liver as well as the prostate. Previously, EAF2 was determined to be a binding partner of VHL and loss of EAF2 induced a reduction in pVHL levels and an increase in hypoxia induced factor 1 alpha (HIF1 alpha) levels in vitro. Here we characterized the cooperative effects of VHL- and EAF2-deficiency on angiogenesis in the liver and prostate of male mice. VHL deficiency consistently increased the incidence of hepatic vascular lesions across three mouse strains. These vascular lesions where characterized by an increase in microvessel density, and staining intensity of VHL target proteins HIF1 alpha and VEGF. EAF2(-/-)VHL(+/-) mice had increased incidence of proliferative hepatic vascular lesions (4/4) compared to VHL(+/-) (10/18) and EAF2(-/-) (0/5) mice. Prostates of EAF2(-/-)VHL(+/-) mice also displayed an increase in microvessel density, as well as stromal inflammation and prostatic intraepithelial neoplasia. These results suggest that cooperation of VHL and EAF2 may be critical for angiogenic regulation of the liver and prostate, and concurrent loss of these two tumor suppressors may result in a pro-angiogenic phenotype.
英文摘要	Von Hippel-Lindau (VHL) disease results from the inactivation of the VHL gene and is characterized by highly vascular tumors. A consequence of VHL loss is the stabilization of hypoxia-inducible factor (HIF) alpha subunits and increased expression of HIF target genes, which include pro-angiogenic growth factors such as vascular endothelial growth factor (VEGF). In mice, homozygous deletion of VHL is embryonic lethal due to vascular abnormalities in the placenta; and, VHL+/- mice develop proliferative vascular lesions in several major organs, most prominently the liver. Loss of ELL-associated factor (EAF2) in murine models has also been shown to induce increased vascular density in the liver as well as the prostate. Previously, EAF2 was determined to be a binding partner of VHL and loss of EAF2 induced a reduction in pVHL levels and an increase in hypoxia induced factor 1 alpha (HIF1 alpha) levels in vitro. Here we characterized the cooperative effects of VHL- and EAF2-deficiency on angiogenesis in the liver and prostate of male mice. VHL deficiency consistently increased the incidence of hepatic vascular lesions across three mouse strains. These vascular lesions where characterized by an increase in microvessel density, and staining intensity of VHL target proteins HIF1 alpha and VEGF. EAF2(-/-)VHL(+/-) mice had increased incidence of proliferative hepatic vascular lesions (4/4) compared to VHL+/- (10/18) and EAF2(-/-) (0/5) mice. Prostates of EAF2(-/-)VHL(+/-) mice also displayed an increase in microvessel density, as well as stromal inflammation and prostatic intraepithelial neoplasia. These results suggest that cooperation of VHL and EAF2 may be critical for angiogenic regulation of the liver and prostate, and concurrent loss of these two tumor suppressors may result in a pro-angiogenic phenotype.
学科主题	Cardiovascular System & Cardiology
WOS标题词	Science & Technology ; Life Sciences & Biomedicine
类目[WOS]	Peripheral Vascular Disease
研究领域[WOS]	Cardiovascular System & Cardiology
关键词[WOS]	HYPOXIA-INDUCIBLE FACTOR-1-ALPHA ; TUMOR-SUPPRESSOR ; CONDITIONAL INACTIVATION ; HEPATOCELLULAR-CARCINOMA ; VASCULAR TUMORS ; DEFICIENT MICE ; VHL GENE ; EXPRESSION ; HIF-1-ALPHA ; PROTEIN
收录类别	SCI
资助信息	[T32 DK007774]; [R37 DK51193]; [R01CA120386]; [CA78335]; [CA125930]
语种	英语
WOS记录号	WOS:000293922300010
公开日期	2011-11-09
内容类型	期刊论文
源URL	[http://ir.ihb.ac.cn/handle/342005/16353]
专题	水生生物研究所_水生生物分子与细胞生物学研究中心_期刊论文
作者单位	1.Univ Pittsburgh, Sch Med, Dept Urol, Pittsburgh, PA 15232 USA 2.Univ Pittsburgh, Div Lab Anim Resources, Univ Pittsburgh Canc Inst, Pittsburgh, PA 15261 USA 3.Chinese Acad Sci, Inst Hydrobiol, Wuhan 430072, Peoples R China 4.Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15232 USA
推荐引用方式 GB/T 7714	Pascal, Laura E.,Ai, Junkui,Rigatti, Lora H.,et al. EAF2 loss enhances angiogenic effects of Von Hippel-Lindau heterozygosity on the murine liver and prostate[J]. ANGIOGENESIS,2011,14(3):331-343.
APA	Pascal, Laura E..,Ai, Junkui.,Rigatti, Lora H..,Lipton, Anne K..,Xiao, Wuhan.,...&Wang, Zhou.(2011).EAF2 loss enhances angiogenic effects of Von Hippel-Lindau heterozygosity on the murine liver and prostate.ANGIOGENESIS,14(3),331-343.
MLA	Pascal, Laura E.,et al."EAF2 loss enhances angiogenic effects of Von Hippel-Lindau heterozygosity on the murine liver and prostate".ANGIOGENESIS 14.3(2011):331-343.