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KRAS mutation-induced EndMT of brain arteriovenous malformation is mediated through the TGF-β/BMP-smad4 pathway

Stroke & Vascular Neurology 2023年第3期8卷 197-206,I0006-I0027页

作者： Hongyuan Xu Ran Huo Hao Li Yuming Jiao Jiancong Weng Jie Wang Zihan Yan Junze Zhang Shaozhi Zhao Qiheng He Yingfan Sun Shuo Wang Yong Cao Department of Neurosurgery Beijing Tiantan HospitalCapital medical universityBeijingChina China National Clinical Research Center for Neurological Diseases BeijingChina Beijing Neurosurgical Institute Capital Medical UniversityBeijingChina

Objective Somatic KRAS mutations have been identified in the majority of brain arteriovenous malformations(bAVMs),and subsequent in vivo experiments have confirmed that KRAS mutation in endothelial cells(ECs)causes AVMs in mouse and zebrafish *** previous study demonstrated that the KRASG12D mutant independently induced the endothelial-mesenchymal transition(EndMT),which was reversed by treatment with the lipid-lowering drug ***,the underlying mechanisms of action were *** We used human umbilical vein ECs(HUVECs)overexpressing the KRASG12D mutant for Western blotting,quantitative real-time PCR,and immunofluorescence and wound healing assays to evaluate the EndMT and determine the activation of downstream *** of smad4 by RNA interference was performed to explore the role of smad4 in regulating the *** ECs expressing the KRASG12D mutant were obtained to verify the smad4 ***,we performed a coimmunoprecipitation assay to probe the mechanism by which lovastatin affects *** HUVECs infected with KRASG12D adenovirus underwent the *** growth factor beta(TGF-β)and bone morphogenetic protein(BMP)signalling pathways were activated in the KRASG12D-mutant HUVECs and ECs in bAVM *** down smad4 expression in both KRASG12D-mutant HUVECs and ECs in bAVM tissues inhibited the *** attenuated the EndMT by downregulating p-smad2/3,p-smad1/5 and acetylated smad4 expression in KRASG12D-mutant *** Our findings suggest that the KRASG12D mutant induces the EndMT by activating the ERK-TGF-β/BMP-smad4 signalling pathway and that lovastatin inhibits the EndMT by suppressing TGF-β/BMP pathway activation and smad4 acetylation.

关键词： KRAS smad4 inhibited

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ALK-mediated Tyr95 phosphorylation of smad4 impairs its transcription activity and the tumor suppressive activity of TGF-β

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Science China(Life Sciences) 2019年第3期62卷 431-432页

作者： Qiaoni Shi Ye-Guang Chen The State Key Laboratory of Membrane Biology Tsinghua-Peking Center for Life Sciences School of Life Sciences Tsinghua University

Transforming growth factorβ(TGF-β)regulates various physiological processes such as cell proliferation,differentiation,morphogenesis,andt tissue homeostasis and *** deregulation of these processes leads to many types of human diseases such as cancer(Massague,2008).TGF-βsignaling is initiated upon active TGF-βdimer binding to the type II receptor TβRII and the type I receptor TβRI on cell surface.

关键词： TGF-β smad4 its

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Imatinib blocks tyrosine phosphorylation of smad4 and restores TGF-β growth-suppressive signaling in BCR-ABL1-positive leukemia

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Signal Transduction and Targeted Therapy 2023年第4期8卷 1993-2006页

作者： Lijing Wang Shuchen Gu Fenfang Chen Yi Yu Jin Cao Xinran Li Chun Gao Yanzhen Chen Shuchong Yuan Xia Liu Jun Qin Bin Zhao Pinglong Xu Tingbo Liang Hongyan Tong Xia Lin Xin-Hua Feng The MOE Key Laboratory of Biosystems Homeostasis&Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology Life Sciences InstituteZhejiang UniversityHangzhouZhejiang 310058China Center for Life Sciences Shaoxing InstituteZhejiang UniversityShaoxingZhejiang 321000China Cancer Center Zhejiang UniversityHangzhouZhejiang 310058China ZJU-Hangzhou Global Scientific and Technological Innovation Center Zhejiang UniversityHangzhouZhejiang 311200China Department of Hematology The First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Beijing Proteome Research Center National Center for Protein SciencesBeijingChina Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease The First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China The Second Affiliated Hospital Zhejiang UniversityHangzhouZhejiang 310009China

Loss of TGF-β-mediated growth suppression is a major contributor to the development of cancers,best exemplified by loss-offunction mutations in genes encoding components of the TGF-βsignaling pathway in colorectal and pancreatic ***,gain-of-function oncogene mutations can also disrupt antiproliferative TGF-β***,the molecular mechanisms underlying oncogene-induced modulation of TGF-βsignaling have not been extensively ***,we show that the oncogenic BCR-ABL1 of chronic myelogenous leukemia(CML)and the cellular ABL1 tyrosine kinases phosphorylate and inactivate smad4 to block antiproliferative TGF-β***,phosphorylation of smad4 at Tyr195,Tyr301,and Tyr322 in the linker region interferes with its binding to the transcription co-activator p300/CBP,thereby blocking the ability of smad4 to activate the expression of cyclin-dependent kinase(CDK)inhibitors and induce cell cycle *** contrast,the inhibition of BCR-ABL1 kinase with Imatinib prevented smad4 tyrosine phosphorylation and re-sensitized CML cells to TGF-β-induced antiproliferative and pro-apoptotic ***,expression of phosphorylation-site-mutated Y195F/Y301F/Y322F mutant of smad4 in smad4-null CML cells enhanced antiproliferative responses to TGF-β,whereas the phosphorylation-mimicking Y195E/Y301E/Y322E mutant interfered with TGF-βsignaling and enhanced the in vivo growth of CML *** findings demonstrate the direct role of BCR-ABL1 tyrosine kinase in suppressing TGF-βsignaling in CML and explain how Imatinib-targeted therapy restored beneficial TGF-βanti-growth responses.

关键词： smad4 phosphorylation thereby

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MiR-146a-5p targeting smad4 and TRAF6 inhibits adipogenensis through TGF-β and AKT/mTORC1 signal pathways in porcine intramuscular preadipocytes

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Journal of Animal Science and Biotechnology 2021年第1期12卷 220-235页

作者： Que Zhang Rui Cai Guorong Tang Wanrong Zhang Weijun Pang Laboratory of Animal Fat Deposition and Muscle Development College of Animal Science and TechnologyNorthwest A&F UniversityYangling 712100ShaanxiChina

Background: Intramuscular fat(IMF) content is a vital parameter for assessing pork quality. Increasing evidence has shown that microRNAs(miRNAs) play an important role in regulating porcine IMF deposition. Here, a novel miRNA implicated in porcine IMF adipogenesis was found, and its effect and regulatory mechanism were further explored with respect to intramuscular preadipocyte proliferation and ***: By porcine adipose tissue miRNA sequencing analysis, we found that miR-146a-5p is a potential regulator of porcine IMF adipogenesis. Further studies showed that miR-146a-5p mimics inhibited porcine intramuscular preadipocyte proliferation and differentiation, while the miR-146a-5p inhibitor promoted cell proliferation and adipogenic differentiation. Mechanistically, miR-146a-5p suppressed cell proliferation by directly targeting smad family member 4(smad4) to attenuate TGF-β signaling. Moreover, miR-146a-5p inhibited the differentiation of intramuscular preadipocytes by targeting TNF receptor-associated factor 6(TRAF6) to weaken the AKT/mTORC1 signaling downstream of the TRAF6 ***: MiR-146a-5p targets smad4 and TRAF6 to inhibit porcine intramuscular adipogenesis by attenuating TGF-β and AKT/mTORC1 signaling, respectively. These findings provide a novel miRNA biomarker for regulating intramuscular adipogenesis to promote pork quality.

关键词： Adipogenesis AKT/mTORC1 signal pathway MiR-146a-5p Porcine intramuscular fat smad4 TGF-βsignal pathway TRAF6

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Expression and localization of smadl, smad2 and smad4 proteins in rat testis during postnatal development

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Asian Journal of Andrology 2003年第1期5卷 51-55页

作者： JingHU Yuan-QiangZHANG Xin-PingLIU Rui-AnWANG YanJIN Ruo-JunXU DepartmentofHistologyandEmbryology DepartmentofBiochemistryandMolecularBiology DepartmentofOralHistologyandPathology SchoolofDentistryFourthMilitaryMedicalUniversityXi‘an710032China DepartmentofZoology UniversityofHongKongHongKongHKSARChina

Aim: To study the expression and regulation of smadl, smad2 and smad4 proteins (intracellular signaling molecules of transforming growth factor-β family) in rat testis during postnatal development. Methods: The whole testes were collected from SD rats aged 3, 7, 14, 28 and 90 (adult) days. The cellular localization and developmental changes were examined by immunohistochemistry ABC method with the glucose oxidase-DAB-nickel enhancement technique. Quantitative analysis of the immunostaining was made by the image analysis system. The smads proteins coexistence in the adult rat testis was tested by the double immune staining for CD14-smad4 and smad2-smad4. The protein expression of smad during rat testicular development was examined by means of Western blots. Results: smadl, smad2 and smad4 were present throughout testicular development. The immunostaining of smadl and smad2 were present in spermatogenic cells. A positive immunoreactivity was located at the cytoplasm, but the nucleus was negative. smadl was immunolocalized at the d14, d28 and adult testes, while smad2, at the d7, d14, d28 and adult testis. There was positive irnmunoreaction in the Sertoli cells and Leydig cells as well. The immunolocalization of smad4 was exclusively at the cytoplasm of Leydig cells and the nuclei were negative throughout the testicular development. No expression was detected in the germ cells. The results of image and statistical analysis showed that generally the expression of smadl, smad2 and smad4 in the testis tended to increase gradually with the growth of the rat. Conclusion: The present data provide direct evidences for the molecular mechanism of TGF-βaction in rat testes during postnatal development and spermatogenesis.

关键词： TGF-β smadl smad2 smad4 testis

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Role of smad4 from ocular surface ectoderm in retinal vasculature development

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International Journal of Ophthalmology(English edition) 2020年第2期13卷 231-238页

作者： Jing Li Jin-Song Zhang Jiang-Yue Zhao Guo-Ge Han Tianjin Eye Hospital Tianjin Eye InstituteTianjin Key Lab of Ophthalmology and Visual ScienceNankai UniversityTianjin 300000China Shenyang Aier Excellence Eye Hospital Shenyang 110000Liaoning ProvinceChina Department of Ophthalmology the Fourth Affiliated Hospital of China Medical UniversityEye Hospital of China Medical UniversityKey Lens Research LaboratoryShenyang 110000Liaoning ProvinceChina

●AIM:To investigate how signals from lens regulate retinal vascular development and neovascularization.●METHODS:Le-Cre transgenic mouse line was employed to inactivate smad4 in the surface ectoderm *** histological and whole-mount retina staining were employed to reveal morphological changes of retinal vasculature in smad4 defective *** microarray and subsequent analyses were conducted to investigate the molecular mechanism underlying the vascular *** polymerase chain reaction(qPCR)was carried out to verify the microarrays results.●RESULTS:We found that inactivation of smad4 specifically on surface ectoderm leads to a variety of retinal vasculature *** analyses and qPCR revealed that Sema3 c,Sema3 e,Nrp1,Tie1,Sox7,Sox17,and Sox18 are significantly affected in the knockout retinas at different developmental stages,suggesting that ocular surface ectoderm-derived smad4 can signal to the retina and regulates various angiogenic signaling in the retina.●CONCLUSION:Our data suggest that the cross-talk between ocular surface ectoderm and retina is important for retinal vasculature development,and smad4 regulates various signaling associated with sprouting angiogenesis,vascular remodeling and maturation in the retina of mice.

关键词： smad4 retinal vasculature surface ectoderm

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Bcl6 Suppresses Cardiac Fibroblast Activation and Function via Directly Binding to smad4

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Current Medical Science 2019年第4期39卷 534-540页

作者： Jian NI Qing-qing WU Hai-han LIAO Di FAN Qi-zhu TANG Department of Cardiology Renmin Hospital of Wuhan UniversityWuhan 430060China Cardiovascular Research Institute of Wuhan University Wuhan 430060China Hubei Key Laboratory of Cardiology Wuhan 430060China

Bcl6,a critical pro-oncogene of human B-cell lymphomas,can promote tumor *** studies have found that Bcl6 participates in hypoxia injury in ***,the effect of Bcl6 on cardiac fibroblasts is still *** aim of this study was to elucidate the functional role of Bcl6 in cardiac fibroblast activation and *** neonatal rat cardiac fibroblasts were isolated and ***,transforming growth factor β1 (TGFβ1) was used to stimulate fibroblast activation.A decreased expression level of Bcl6 was observed in fibroblasts after stimulation with TGFβ***,cells were transfected with adenovirus Bcl6 to overexpress *** results showed that Bcl6 overexpression induced decreased proliferation and reduced activation of fibroblasts which were stimulated with TGFβ*** was found that activated smad2 and smad3 were not changed by overexpressing Bcl6,but smad4 was ***,co-immunoprecipitation results showed that Bcl6 directly bound to smad4,and induced down-regulation of *** last,smad4 activator could counteract the anti-fibroblast effects of *** conclusion,Bcl6 may negatively regulate cardiac fibroblast activation and function by directly binding to smad4.

关键词： Bcl6 cardiac fibroblast transforming growth factor β1 smad4

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EXPRESSION AND LOCALIZATION OF smad4 PROTEIN IN RAT TESTIS DURING THE POSTNATAL DEVELOPMENT

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Chinese Medical Sciences Journal 2003年第3期18卷 155-161页

作者：张远强胡静刘新平许若军 Department of Histology and Embryology Fourth Military Medical University Xi'an710032 Biochemistry and Molecular Biology Fourth Military Medical University Xi'a n710032 Department of Zoology University of Hong Kong Hong Kong

*** study expression and localiza tion of smad4protein,the common-mediator smad,which is one of intracellular signaling molecules of transforming growth factor-afamily,in rat t estis during postnatal *** this study,whole testes were co llected from S.D rats aged3days,7days,14days and28days,and adult respe *** examined the cellular localization and developmental change of smad 4in rat testis by immunohistochemical ABC method with glucose oxidase-DAB-nic kel enhancement technique;the quantitative analysis of the immunostaining by t he image analysis system;the smads pro-teins coexistence in the adult rat test is by the double immune staining for CD14-smad4and smad2-smad4;the prote in expression of smad during rat testicular development by means of Western blo *** protein of smad4was present in rats from3days of age to adul thood,and the im-munolocalization was exclusively localized to the cytoplasm o f Leydig cells with negative nuclei in the in-terstitial tissue at any time po *** expression was detected in germ *** result of image and sta-tis tical analysis showed that generally,there was a tendency that the expression o f smad4in the testes increased gradually with the rats developing maturation.C *** data provide direct evidence for the molecular mechanism of TGF-aaction in rat testes during postnatal development and spermatogenesis of ra ts.

关键词： tran sf orming growth factor smad4 testis

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Anterior segment dysgenesis correlation with epithelial-mesenchymal transition in smad4 knockout mice

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International Journal of Ophthalmology(English edition) 2016年第7期9卷 943-947页

作者： Jing Li Yu Qin Fang-Kun Zhao Di Wu Xue-Fei He Jia Liu Jiang-Yue Zhao Jin-Song Zhang Department of Ophthalmology the Fourth Affiliated Hospital of China Medical University Eye Hospital of China Medical University Key Lens Research Laboratory of Liaoning Province The Shenyang Fourth People's Hospital Shenyang Eye Research Institute Department of Ophthalmology Ningbo No.2 Hospital

AIM： To explore the molecular mechanisms in lens development and the pathogenesis of Peters anomaly in smad4 defective mice. METHODS： Le-Cre transgenic mouse line was employed to inactivate smad4 in the surface ectoderm selectively. Pathological techniques were used to reveal the morphological changes of the anterior segment in smad4 defective eye. Immunohistochemical staining was employed to observe the expression of E-cadherin, N- cadherin and α-SMA in anterior segment of smad4 defective mice and control mice at embryonic （E） day 16.5. Real-time quantitative polymerase chain reaction （qPCR） was performed to detect the expression of Snail, Zebl, Zeb2 and Twist2 in lens of smad4 defective mice and control mice at E16.5. RESULTS： Conditional deletion of smad4 on eye surface ectoderm resulted in corneal dysplasia, iridocorneal angle closure, corneolenticular adhesions and cataract resembling Peters anomaly. Loss of smad4 function inhibited E-cadherin expression in the lens epithelium cells and corneal epithelium cells in smad4 defective eye. Expression of N-cadherin was upregulated in corneal epithelium and corneal stroma. Both E-cadherin and N-cadherin were down-regulated at the future trabecular meshwork region in mutant eye. The qPCR results showed that the expression of Twist2 was increased significantly in the mutant lens （P〈0.01）. CONCLUSION： smad4 is essential to eye development and likely a candidate pathogenic gene to Peters anomaly by regulating epithelial-mesenchymal transition. Twist2 can be regulated by smad4 and plays an essential role in lens development.

关键词： Peters anomaly anterior segment dysgenesis smad4 N-cadherin Twist2

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TRANSFORMING GROWTH FACTOR-β1 AND smad4 SIGNALING PATHWAY DOWN-REGULATES RENAL EXTRACELLULAR MATRIX DEGRADATION IN DIABETIC RATS

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Chinese Medical Sciences Journal 2007年第4期22卷 243-249页

作者： Qin Yang Ru-jia Xie Ting Yang Li Fang Bing Han Guo-zhong Zhang Ming-liang Cheng Department of Pathophysiology Guiyang Medical College Guiyang 550004 Department of Infectious Diseases Affiliated Hospital of Guiyang Medical College Guiyang 550004

Objective To investigate the role of transforming growth factor-131 （TGF-β1）/smad4 pathway in development of renal fibrosis in streptozotocin （STZ）-induced diabetic nephropathy （DN） rats and explore its possible mechanism. Methods Male Wistar rats weighing 180-220 g were divided into 5 groups： group A （ normal control）, group B [ diabetes mellitus （DM） 2 weeks ], group C （ DM 4 weeks）, group D （ DM 8 weeks）, and group E （ DM 16 weeks）. Except for the normal control group, other groups were induced DM by single injection of STZ （55 mg/kg） respectively. Blood glucose level, serum creatinine, and 24-hour urine protein were examined. Expressions of TGF-β1 and smad4 protein and mRNA in kidney were detected using immunohistochemical technique, Western blot, and real-time PCR. mRNA expressions of stromelysin-1 （ MMP-3 ）, tissue inhibitor of metalloproteinase-1 （ TIMP-1 ）, and collagen Ⅲ in kidney were also detected by real-time PCR. Results The levels of blood glucose, serum creatinine, and 24-hour urine protein in rats of group B, C, D, and E were higher than those of the control group. With the progression of renal fibrosis, the expressions of TGF-β1 and smad4 protein and mRNA in kidney of diabetic rats elevated. In addition, the renal MMP-3 mRNA expression diminished in diabetic rats, while TIMP-1 and collagen Ⅲ mRNA increased. Conclusions In STZ-induced diabetic rats, the TGF-β1/smad4 appears to play an important role in renal fibrosis of DN. The increased expression of TGF-β1 and smad4 might result in the transcriptional regulation of downstream target genes of TGF-β1/smad4 pathway, which contributes to the progression of renal fibrosis in diabetic rats.

关键词： transforming growth factor-β1 smad4 diabetes mellitus renal fibrosis

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