General Information of the Ferroptosis Regulator (ID: REG10122)
Regulator Name mRNA decay activator protein ZFP36 (ZFP36)
Synonyms
G0/G1 switch regulatory protein 24; Growth factor-inducible nuclear protein NUP475
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Gene Name ZFP36
Gene ID 7538
Regulator Type Protein coding
Uniprot ID P26651
Sequence
MDLTAIYESLLSLSPDVPVPSDHGGTESSPGWGSSGPWSLSPSDSSPSGVTSRLPGRSTS
LVEGRSCGWVPPPPGFAPLAPRLGPELSPSPTSPTATSTTPSRYKTELCRTFSESGRCRY
GAKCQFAHGLGELRQANRHPKYKTELCHKFYLQGRCPYGSRCHFIHNPSEDLAAPGHPPV
LRQSISFSGLPSGRRTSPPPPGLAGPSLSSSSFSPSSSPPPPGDLPLSPSAFSAAPGTPL
ARRDPTPVCCPSCRRATPISVWGPLGGLVRTPSVQSLGSDPDEYASSGSSLGGSDSPVFE
AGVFAPPQPVAAPRRLPIFNRISVSE

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Function
Zinc-finger RNA-binding protein that destabilizes several cytoplasmic AU-rich element (ARE)-containing mRNA transcripts by promoting their poly(A) tail removal or deadenylation, and hence provide a mechanism for attenuating protein synthesis. Acts as an 3'-untranslated region (UTR) ARE mRNA-binding adapter protein to communicate signaling events to the mRNA decay machinery. Recruits deadenylase CNOT7 (and probably the CCR4-NOT complex) via association with CNOT1, and hence promotes ARE-mediated mRNA deadenylation. Functions also by recruiting components of the cytoplasmic RNA decay machinery to the bound ARE-containing mRNAs. Self regulates by destabilizing its own mRNA. Binds to 3'-UTR ARE of numerous mRNAs and of its own mRNA. Plays a role in anti-inflammatory responses; suppresses tumor necrosis factor (TNF)-alpha production by stimulating ARE-mediated TNF-alpha mRNA decay and several other inflammatory ARE- containing mRNAs in interferon (IFN)- and/or lipopolysaccharide (LPS)- induced macrophages. Also plays a role in the regulation of dendritic cell maturation at the post-transcriptional level, and hence operates as part of a negative feedback loop to limit the inflammatory response. Promotes ARE-mediated mRNA decay of hypoxia-inducible factor HIF1A mRNA during the response of endothelial cells to hypoxia. Positively regulates early adipogenesis of preadipocytes by promoting ARE-mediated mRNA decay of immediate early genes (IEGs). Negatively regulates hematopoietic/erythroid cell differentiation by promoting ARE-mediated mRNA decay of the transcription factor STAT5B mRNA. Plays a role in maintaining skeletal muscle satellite cell quiescence by promoting ARE-mediated mRNA decay of the myogenic determination factor MYOD1 mRNA. Associates also with and regulates the expression of non-ARE-containing target mRNAs at the post-transcriptional level, such as MHC class I mRNAs. Participates in association with argonaute RISC catalytic components in the ARE-mediated mRNA decay mechanism; assists microRNA (miRNA) targeting ARE-containing mRNAs. May also play a role in the regulation of cytoplasmic mRNA decapping; enhances decapping of ARE-containing RNAs, in vitro. Involved in the delivery of target ARE-mRNAs to processing bodies (PBs). In addition to its cytosolic mRNA-decay function, affects nuclear pre-mRNA processing. Negatively regulates nuclear poly(A)-binding protein PABPN1-stimulated polyadenylation activity on ARE-containing pre-mRNA during LPS- stimulated macrophages. Also involved in the regulation of stress granule (SG) and P-body (PB) formation and fusion. Plays a role in the regulation of keratinocyte proliferation, differentiation and apoptosis. Plays a role as a tumor suppressor by inhibiting cell proliferation in breast cancer cells.

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HGNC ID
HGNC:12862
KEGG ID hsa:7538
Full List of the Ferroptosis Target of This Regulator and Corresponding Disease/Drug Response(s)
ZFP36 can regulate the following target(s), and cause disease/drug response(s). You can browse detail information of target(s) or disease/drug response(s).
Browse Target
Browse Disease
Browse Drug
Nuclear receptor coactivator 4 (NCOA4) [Driver]
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Target for Ferroptosis Driver
Responsed Disease Liver fibrosis ICD-11: DB93
Responsed Drug Sorafenib Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model
hHSCs (Human hepatic stellate cells)
In Vivo Model
Fifty-six 8-week-old male C57BL/6 mice were obtained from the Experimental Animal Center of Yangzhou University (Yangzhou, China). Controls underwent a sham operation that consisted of exposure, but not ligation, of the common bile duct. Erastin (30 mg/kg, once every other day) and sorafenib (10 mg/kg, once every other day) were suspended in sterile phosphate-buffered saline (PBS; Sigma, P5368) and given by intraperitoneal injection for 2 weeks after the BDL operation. VA-Lip-control-vector and VA-Lip-Zfp36-plasmid (0.75 mg/kg) were administered intravenously 3 times a week for 2 weeks after the BDL operation.

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Response regulation Sorafenib monotherapy led to ZFP36 downregulation, ferritinophagy activation, and ferroptosis induction in human HSCs. ZFP36 plasmid markedly upregulated, whereas FBXW7 plasmid apparently downregulaed, ferritin and NCOA4 expression in sorafenib-treated HSC-LX2 cells. The study identified ZFP36-autophagy-dependent ferroptosis as a potential target for the treatment of liver fibrosis.
Liver fibrosis [ICD-11: DB93]
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator mRNA decay activator protein ZFP36 (ZFP36) Protein coding
Responsed Drug Sorafenib Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model
hHSCs (Human hepatic stellate cells)
In Vivo Model
Fifty-six 8-week-old male C57BL/6 mice were obtained from the Experimental Animal Center of Yangzhou University (Yangzhou, China). Controls underwent a sham operation that consisted of exposure, but not ligation, of the common bile duct. Erastin (30 mg/kg, once every other day) and sorafenib (10 mg/kg, once every other day) were suspended in sterile phosphate-buffered saline (PBS; Sigma, P5368) and given by intraperitoneal injection for 2 weeks after the BDL operation. VA-Lip-control-vector and VA-Lip-Zfp36-plasmid (0.75 mg/kg) were administered intravenously 3 times a week for 2 weeks after the BDL operation.

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Response regulation Sorafenib monotherapy led to ZFP36 downregulation, ferritinophagy activation, and ferroptosis induction in human HSCs. ZFP36 plasmid markedly upregulated, whereas FBXW7 plasmid apparently downregulaed, ferritin and NCOA4 expression in sorafenib-treated HSC-LX2 cells. The study identified ZFP36-autophagy-dependent ferroptosis as a potential target for the treatment of liver fibrosis.
Sorafenib [Investigative]
In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response [1]
Drug for Ferroptosis Inducer
Response Target Nuclear receptor coactivator 4 (NCOA4) Driver
Responsed Disease Liver fibrosis ICD-11: DB93
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model
hHSCs (Human hepatic stellate cells)
In Vivo Model
Fifty-six 8-week-old male C57BL/6 mice were obtained from the Experimental Animal Center of Yangzhou University (Yangzhou, China). Controls underwent a sham operation that consisted of exposure, but not ligation, of the common bile duct. Erastin (30 mg/kg, once every other day) and sorafenib (10 mg/kg, once every other day) were suspended in sterile phosphate-buffered saline (PBS; Sigma, P5368) and given by intraperitoneal injection for 2 weeks after the BDL operation. VA-Lip-control-vector and VA-Lip-Zfp36-plasmid (0.75 mg/kg) were administered intravenously 3 times a week for 2 weeks after the BDL operation.

    Click to Show/Hide
Response regulation Sorafenib monotherapy led to ZFP36 downregulation, ferritinophagy activation, and ferroptosis induction in human HSCs. ZFP36 plasmid markedly upregulated, whereas FBXW7 plasmid apparently downregulaed, ferritin and NCOA4 expression in sorafenib-treated HSC-LX2 cells. The study identified ZFP36-autophagy-dependent ferroptosis as a potential target for the treatment of liver fibrosis.
References
Ref 1 RNA-binding protein ZFP36/TTP protects against ferroptosis by regulating autophagy signaling pathway in hepatic stellate cells. Autophagy. 2020 Aug;16(8):1482-1505. doi: 10.1080/15548627.2019.1687985. Epub 2019 Nov 11.