The Rho family of GTPases is strictly regulated by a large family of GTPase-activating proteins(GAPs)that stimulate the relatively weak intrinsic GTP-hydrolyzing activity of Rho GTPases.p190A is a potent and widely ex...The Rho family of GTPases is strictly regulated by a large family of GTPase-activating proteins(GAPs)that stimulate the relatively weak intrinsic GTP-hydrolyzing activity of Rho GTPases.p190A is a potent and widely expressed GAP that acts on RhoA GTPases.p190A is frequently mutated in endometrial cancer,but the contribution of p190A mutations to endometrial tumorigenesis remains unclear.Here we identified that p190A is an upstream regulator of the Hippo-YAP signaling pathway,which is a critical regulator of cell proliferation,apoptosis,and cell fate.p190A knockout in endometrial cancer cells promoted cell proliferation,migration,and epithelial–mesenchymal transition(EMT),which were partially dependent on YAP activation.Wild-type p190A,but not endometrial cancer-associated mutants,suppressed the nuclear localization,transcriptional activity,and malignant transformation function of YAP.Moreover,the nuclear localization of YAP was enhanced in p190A-mutated endometrial cancer.These findings reveal novel molecular mechanisms underlying Hippo-YAP pathway-driven endometrial tumorigenesis and elucidate the potential for therapy targeting the Hippo-YAP pathway in p190A-mutated endometrial cancer.展开更多
The current coronavirus disease 2019(COVID-19)pandemic caused by severe acute respiratory syndrome coronavirus(SARS-CoV-2)remains a threat to pregnant women.However,the impact of early pregnancy SARS-CoV-2 infection o...The current coronavirus disease 2019(COVID-19)pandemic caused by severe acute respiratory syndrome coronavirus(SARS-CoV-2)remains a threat to pregnant women.However,the impact of early pregnancy SARS-CoV-2 infection on the maternal-fetal interface remains poorly understood.Here,we present a comprehensive analysis of single-cell transcriptomics and metabolomics in placental samples infected with SARS-CoV-2 during early pregnancy.Compared to control placentas,SARS-CoV-2 infection elicited immune responses at the maternal-fetal interface and induced metabolic alterations in amino acid and phospholipid profiles during the initial weeks post-infection.However,subsequent immune cell activation and heightened immune tolerance in trophoblast cells established a novel dynamic equilibrium that mitigated the impact on the maternal-fetal interface.Notably,the immune response and metabolic alterations at the maternal-fetal interface exhibited a gradual decline during the second trimester.Our study underscores the adaptive immune tolerance mechanisms and establishment of immunological balance during the first two trimesters following maternal SARS-CoV-2 infection.展开更多
基金supported by the National Natural Science Foundation of China(numbers 91954106 and 81872109 to K.G.,number 81672574 to X.W.,and number 81601247 to B.L.)the Shanghai Municipal Medical and Health Discipline Construction Projects(number 2017ZZ02015 to X.W.)+1 种基金the Natural Science Foundation of Shanghai(number 18ZR1430100 to K.G.)the Shanghai Clinical Medicine Field Project of Science and Technology Innovation Action Program(number 17411951600 to X.W.).
文摘The Rho family of GTPases is strictly regulated by a large family of GTPase-activating proteins(GAPs)that stimulate the relatively weak intrinsic GTP-hydrolyzing activity of Rho GTPases.p190A is a potent and widely expressed GAP that acts on RhoA GTPases.p190A is frequently mutated in endometrial cancer,but the contribution of p190A mutations to endometrial tumorigenesis remains unclear.Here we identified that p190A is an upstream regulator of the Hippo-YAP signaling pathway,which is a critical regulator of cell proliferation,apoptosis,and cell fate.p190A knockout in endometrial cancer cells promoted cell proliferation,migration,and epithelial–mesenchymal transition(EMT),which were partially dependent on YAP activation.Wild-type p190A,but not endometrial cancer-associated mutants,suppressed the nuclear localization,transcriptional activity,and malignant transformation function of YAP.Moreover,the nuclear localization of YAP was enhanced in p190A-mutated endometrial cancer.These findings reveal novel molecular mechanisms underlying Hippo-YAP pathway-driven endometrial tumorigenesis and elucidate the potential for therapy targeting the Hippo-YAP pathway in p190A-mutated endometrial cancer.
基金supported by the Ministry of Science and Technology of China(2022YFC2702200,2021YFA1102900)the National Natural Science Foundation of China(Grant Nos.82022027,32270909,31721003,92168205,31871448,31820103009,and 32300684)+5 种基金supported by the key project of the Science and Technology of Shanghai Municipality(19JC1415300 and 21JC1405500)the Shanghai Municipal Medical and Health Discipline Construction Projects(2017ZZ02015)China Postdoctoral Science Foundation(2023M732660)the Postdoctoral Fellowship Program of CPSF(GZB20230523)Shanghai Municipal Health(Grant No.20214Y0254)Shanghai Pilot Program for Basic Research,Shanghai“Medical Academy Rising Star”Young Medical Talents Program,Shanghai First Maternity and Infant Hospital“Talent Reservoir”Sailing Program and the Fundamental Research Funds for the Central Universities.
文摘The current coronavirus disease 2019(COVID-19)pandemic caused by severe acute respiratory syndrome coronavirus(SARS-CoV-2)remains a threat to pregnant women.However,the impact of early pregnancy SARS-CoV-2 infection on the maternal-fetal interface remains poorly understood.Here,we present a comprehensive analysis of single-cell transcriptomics and metabolomics in placental samples infected with SARS-CoV-2 during early pregnancy.Compared to control placentas,SARS-CoV-2 infection elicited immune responses at the maternal-fetal interface and induced metabolic alterations in amino acid and phospholipid profiles during the initial weeks post-infection.However,subsequent immune cell activation and heightened immune tolerance in trophoblast cells established a novel dynamic equilibrium that mitigated the impact on the maternal-fetal interface.Notably,the immune response and metabolic alterations at the maternal-fetal interface exhibited a gradual decline during the second trimester.Our study underscores the adaptive immune tolerance mechanisms and establishment of immunological balance during the first two trimesters following maternal SARS-CoV-2 infection.
