Zinc finger protein 36(ZFP36)was found to be downregulated in osteosarcoma(OS)tumor tissues.We aimed to investigate the roles and mechanisms of ZFP36 in ferroptosis regulation during OS development.Two Gene Expression...Zinc finger protein 36(ZFP36)was found to be downregulated in osteosarcoma(OS)tumor tissues.We aimed to investigate the roles and mechanisms of ZFP36 in ferroptosis regulation during OS development.Two Gene Expression Omnibus(GEO)datasets showed that ZFP36 was a differentially expressed gene(DEG)in OS.Western blot and immunohistochemistry results showed that ZFP36 was downregulated in OS tumors and cell lines.ZFP36 overexpression plasmids and small interfering RNAs(siRNAs)were respectively transfected into OS cells.ZFP36 overexpression restrained proliferation,migration,and invasion in MG63 and U2OS cells,while ZFP36 knockdown displayed the opposite results.Moreover,ZFP36 overexpression increased the levels of intracellular Fe2t,reactive oxygen species(ROS),and malondialdehyde(MDA),and decreased the levels of glutathione(GSH),glutathione peroxidase 4(GPX4),and solute carrier family 7 member 11(SLC7A11).ZFP36 overexpression disturbed mitochondrial membrane potential(MMP)and mitochondrial morphology in OS cells.However,ZFP36 knockdown had the opposite results.Mechanistic studies indicated that ZFP36 promoted E2F transcription factor 1(E2F1)messenger RNA(mRNA)degradation by binding to the AU-rich elements(AREs)within E2F130 untranslated region(30UTR)in OS cells.E2F1 overexpression abrogated the effects of ZFP36 overexpression on malignant progression,ferroptosis,and mitochondrial dysfunction in OS cells.Furthermore,E2F1 promoted the transcription activation of activating transcription factor 4(ATF4)by binding to ATF4 promoter.E2F1 knockdown inhibited malignant progression,and promoted ferroptosis and mitochondrial dysfunction in OS cells,which was abrogated by ATF4 overexpression.Additionally,MG63 cells transfected with lentivirus ZFP36 overexpression vector(Lv-ZFP36)were injected into nude mice and tumor growth was monitored.ZFP36 overexpression significantly suppressed OS tumor growth under in vivo settings.In conclusion,ZFP36 overexpression promoted ferroptosis and mitochondrial dysfunction and inhibited malignant progression in OS by regulating the E2F1/ATF4 axis.We may provide the promising ZFP36 target for OS treatment.展开更多
Xenopus ZFP36L1(zinc finger protein 36,C3H type-like 1)belongs to the ZFP36 family of RNA-binding proteins,which contains two characteristic tandem CCCH-type zinc-finger domains.The ZFP36 proteins can bind AU-rich ele...Xenopus ZFP36L1(zinc finger protein 36,C3H type-like 1)belongs to the ZFP36 family of RNA-binding proteins,which contains two characteristic tandem CCCH-type zinc-finger domains.The ZFP36 proteins can bind AU-rich elements in 3'untranslated regions of target mRNAs and promote their turnover.However,the expression and role of ZFP36 genes during neural development in Xenopus embryos remains largely unknown.The present study showed that Xenopus ZFP36L1 was expressed at the dorsal part of the forebrain,forebrain-midbrain boundary,and midbrain-hindbrain boundary from late neurula stages to tadpole stages of embryonic development.Overexpression of XZFP36L1 in Xenopus embryos inhibited neural induction and differentiation,leading to severe neural tube defects.The function of XZP36L1 requires both its zinc finger and C terminal domains,which also affect its subcellular localization.These results suggest that XZFP36L1 is likely involved in neural development in Xenopus and might play an important role in post-transcriptional regulation.展开更多
Xenopus ZFP36L1 （zinc finger protein 36, C3H type-like 1） belongs to the ZFP36 family of RNA-binding proteins, which contains two characteristic tandem CCCH-type zinc-finger domains. The ZFP36 proteins can bind AU-r...Xenopus ZFP36L1 （zinc finger protein 36, C3H type-like 1） belongs to the ZFP36 family of RNA-binding proteins, which contains two characteristic tandem CCCH-type zinc-finger domains. The ZFP36 proteins can bind AU-rich elements in 3＇ untranslated regions of target mRNAs and promote their turnover. However, the expression and role of ZFP36 genes during neural development in Xenopus embryos remains largely unknown. The present study showed that Xenopus ZFP36L1 was expressed at the dorsal part of the forebrain, forebrain-midbrain boundary, and midbrain-hindbrain boundary from late neurula stages to tadpole stages of embryonic development. Overexpression of XZFP36L1 in Xenopus embryos inhibited neural induction and differentiation, leading to severe neural tube defects. The function of XZP36L1 requires both its zinc finger and C terminal domains, which also affect its subcellular localization. These results suggest that XZFP36L1 is likely involved in neural development in Xenopus and might play an important role in post-transcriptional regulation.展开更多
Aluminum(Al)toxicity poses a significant constraint on field crop yields in acid soils.Zinc finger protein36(ZFP36)is well-documented for its pivotal role in enhancing tolerance to both drought and oxidative stress in...Aluminum(Al)toxicity poses a significant constraint on field crop yields in acid soils.Zinc finger protein36(ZFP36)is well-documented for its pivotal role in enhancing tolerance to both drought and oxidative stress in rice.This study unveils a novel function of ZFP36 modulated by abscisic acid(ABA)-dependent mechanisms,specifically aimed at alleviating Al toxicity in rice.Under Al stress,the expression of ZFP36significantly increased through an ABA-dependent pathway.Knocking down ZFP36 heightened Al sensitivity,while overexpressing ZFP36 conferred increased resistance to Al stress.Additionally,our investigations revealed a physical interaction between ZFP36 and pyruvate dehydrogenase kinase 1 in rice(OsPDK1).Biochemical assays further elucidated that OsPDK1 phosphorylates ZFP36 at the amino acid site 73–161.Subsequent experiments demonstrated that ZFP36 positively regulates the expression of ascorbate peroxidases(OsAPX1)and OsALS1 by binding to specific elements in their upstream segments in rice.Through genetic and phenotypic analyses,we unveiled that OsPDK1 influences ABA-triggered antioxidant defense to alleviate Al toxicity by interacting with ZFP36.In summary,our study underscores that pyruvate dehydrogenase kinase 1(OsPDK1)phosphorylates ZFP36 to modulate the activities of antioxidant enzymes via an ABA-dependent pathway,influencing tolerance of rice to soil Al toxicity.展开更多
基金funding support from the hospital-level project of Taizhou People's Hospital(Project No.:ZL201944).
文摘Zinc finger protein 36(ZFP36)was found to be downregulated in osteosarcoma(OS)tumor tissues.We aimed to investigate the roles and mechanisms of ZFP36 in ferroptosis regulation during OS development.Two Gene Expression Omnibus(GEO)datasets showed that ZFP36 was a differentially expressed gene(DEG)in OS.Western blot and immunohistochemistry results showed that ZFP36 was downregulated in OS tumors and cell lines.ZFP36 overexpression plasmids and small interfering RNAs(siRNAs)were respectively transfected into OS cells.ZFP36 overexpression restrained proliferation,migration,and invasion in MG63 and U2OS cells,while ZFP36 knockdown displayed the opposite results.Moreover,ZFP36 overexpression increased the levels of intracellular Fe2t,reactive oxygen species(ROS),and malondialdehyde(MDA),and decreased the levels of glutathione(GSH),glutathione peroxidase 4(GPX4),and solute carrier family 7 member 11(SLC7A11).ZFP36 overexpression disturbed mitochondrial membrane potential(MMP)and mitochondrial morphology in OS cells.However,ZFP36 knockdown had the opposite results.Mechanistic studies indicated that ZFP36 promoted E2F transcription factor 1(E2F1)messenger RNA(mRNA)degradation by binding to the AU-rich elements(AREs)within E2F130 untranslated region(30UTR)in OS cells.E2F1 overexpression abrogated the effects of ZFP36 overexpression on malignant progression,ferroptosis,and mitochondrial dysfunction in OS cells.Furthermore,E2F1 promoted the transcription activation of activating transcription factor 4(ATF4)by binding to ATF4 promoter.E2F1 knockdown inhibited malignant progression,and promoted ferroptosis and mitochondrial dysfunction in OS cells,which was abrogated by ATF4 overexpression.Additionally,MG63 cells transfected with lentivirus ZFP36 overexpression vector(Lv-ZFP36)were injected into nude mice and tumor growth was monitored.ZFP36 overexpression significantly suppressed OS tumor growth under in vivo settings.In conclusion,ZFP36 overexpression promoted ferroptosis and mitochondrial dysfunction and inhibited malignant progression in OS by regulating the E2F1/ATF4 axis.We may provide the promising ZFP36 target for OS treatment.
基金National Natural Science Foundation of China(90919039,C120106)the National Institute for Basic Biology,Japan,for the Xl073b24 clone.
文摘Xenopus ZFP36L1(zinc finger protein 36,C3H type-like 1)belongs to the ZFP36 family of RNA-binding proteins,which contains two characteristic tandem CCCH-type zinc-finger domains.The ZFP36 proteins can bind AU-rich elements in 3'untranslated regions of target mRNAs and promote their turnover.However,the expression and role of ZFP36 genes during neural development in Xenopus embryos remains largely unknown.The present study showed that Xenopus ZFP36L1 was expressed at the dorsal part of the forebrain,forebrain-midbrain boundary,and midbrain-hindbrain boundary from late neurula stages to tadpole stages of embryonic development.Overexpression of XZFP36L1 in Xenopus embryos inhibited neural induction and differentiation,leading to severe neural tube defects.The function of XZP36L1 requires both its zinc finger and C terminal domains,which also affect its subcellular localization.These results suggest that XZFP36L1 is likely involved in neural development in Xenopus and might play an important role in post-transcriptional regulation.
基金Foundation items： This work was supported by National Natural Science Foundation of China （90919039 C120106） Acknowledgements We thank the National Institute for Basic Biology, Japan, for the X1073h24 clone.
文摘Xenopus ZFP36L1 （zinc finger protein 36, C3H type-like 1） belongs to the ZFP36 family of RNA-binding proteins, which contains two characteristic tandem CCCH-type zinc-finger domains. The ZFP36 proteins can bind AU-rich elements in 3＇ untranslated regions of target mRNAs and promote their turnover. However, the expression and role of ZFP36 genes during neural development in Xenopus embryos remains largely unknown. The present study showed that Xenopus ZFP36L1 was expressed at the dorsal part of the forebrain, forebrain-midbrain boundary, and midbrain-hindbrain boundary from late neurula stages to tadpole stages of embryonic development. Overexpression of XZFP36L1 in Xenopus embryos inhibited neural induction and differentiation, leading to severe neural tube defects. The function of XZP36L1 requires both its zinc finger and C terminal domains, which also affect its subcellular localization. These results suggest that XZFP36L1 is likely involved in neural development in Xenopus and might play an important role in post-transcriptional regulation.
基金provided by the National Natural Science Foundation of China (31901202,31672228)National Distinguished Expert Project (WQ20174400441)+2 种基金the Higher Education Department of Guangdong province (2020KCXTD025)Key Laboratory Project of Guangdong Province (2022B1212010015)the Australian Research Council (DP150101663)。
文摘Aluminum(Al)toxicity poses a significant constraint on field crop yields in acid soils.Zinc finger protein36(ZFP36)is well-documented for its pivotal role in enhancing tolerance to both drought and oxidative stress in rice.This study unveils a novel function of ZFP36 modulated by abscisic acid(ABA)-dependent mechanisms,specifically aimed at alleviating Al toxicity in rice.Under Al stress,the expression of ZFP36significantly increased through an ABA-dependent pathway.Knocking down ZFP36 heightened Al sensitivity,while overexpressing ZFP36 conferred increased resistance to Al stress.Additionally,our investigations revealed a physical interaction between ZFP36 and pyruvate dehydrogenase kinase 1 in rice(OsPDK1).Biochemical assays further elucidated that OsPDK1 phosphorylates ZFP36 at the amino acid site 73–161.Subsequent experiments demonstrated that ZFP36 positively regulates the expression of ascorbate peroxidases(OsAPX1)and OsALS1 by binding to specific elements in their upstream segments in rice.Through genetic and phenotypic analyses,we unveiled that OsPDK1 influences ABA-triggered antioxidant defense to alleviate Al toxicity by interacting with ZFP36.In summary,our study underscores that pyruvate dehydrogenase kinase 1(OsPDK1)phosphorylates ZFP36 to modulate the activities of antioxidant enzymes via an ABA-dependent pathway,influencing tolerance of rice to soil Al toxicity.
