Ferroptosis Regulator Information

General Information of the Ferroptosis Regulator (ID: REG10294)
Regulator Name F-box/WD repeat-containing protein 7 (FBXW7)
Synonyms
Archipelago homolog
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Gene Name FBXW7
Gene ID 55294
Regulator Type Protein coding
Uniprot ID Q969H0
Sequence
MNQELLSVGSKRRRTGGSLRGNPSSSQVDEEQMNRVVEEEQQQQLRQQEEEHTARNGEVV
GVEPRPGGQNDSQQGQLEENNNRFISVDEDSSGNQEEQEEDEEHAGEQDEEDEEEEEMDQ
ESDDFDQSDDSSREDEHTHTNSVTNSSSIVDLPVHQLSSPFYTKTTKMKRKLDHGSEVRS
FSLGKKPCKVSEYTSTTGLVPCSATPTTFGDLRAANGQGQQRRRITSVQPPTGLQEWLKM
FQSWSGPEKLLALDELIDSCEPTQVKHMMQVIEPQFQRDFISLLPKELALYVLSFLEPKD
LLQAAQTCRYWRILAEDNLLWREKCKEEGIDEPLHIKRRKVIKPGFIHSPWKSAYIRQHR
IDTNWRRGELKSPKVLKGHDDHVITCLQFCGNRIVSGSDDNTLKVWSAVTGKCLRTLVGH
TGGVWSSQMRDNIIISGSTDRTLKVWNAETGECIHTLYGHTSTVRCMHLHEKRVVSGSRD
ATLRVWDIETGQCLHVLMGHVAAVRCVQYDGRRVVSGAYDFMVKVWDPETETCLHTLQGH
TNRVYSLQFDGIHVVSGSLDTSIRVWDVETGNCIHTLTGHQSLTSGMELKDNILVSGNAD
STVKIWDIKTGQCLQTLQGPNKHQSAVTCLQFNKNFVITSSDDGTVKLWDLKTGEFIRNL
VTLESGGSGGVVWRIRASNTKLVCAVGSRNGTEETKLLVLDFDVDMK

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Function
Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Recognizes and binds phosphorylated sites/phosphodegrons within target proteins and thereafter brings them to the SCF complex for ubiquitination. Identified substrates include cyclin-E (CCNE1 or CCNE2), DISC1, JUN, MYC, NOTCH1 released notch intracellular domain (NICD), NFE2L1, NOTCH2, MCL1, RICTOR, and probably PSEN1. Acts as a negative regulator of JNK signaling by binding to phosphorylated JUN and promoting its ubiquitination and subsequent degradation. Involved in bone homeostasis and negative regulation of osteoclast differentiation. Regulates the amplitude of the cyclic expression of hepatic core clock genes and genes involved in lipid and glucose metabolism via ubiquitination and proteasomal degradation of their transcriptional repressor NR1D1; CDK1-dependent phosphorylation of NR1D1 is necessary for SCF(FBXW7)-mediated ubiquitination. Also able to promote 'Lys-63'-linked ubiquitination in response to DNA damage. The SCF(FBXW7) complex facilitates double-strand break repair following phosphorylation by ATM: phosphorylation promotes localization to sites of double-strand breaks and 'Lys-63'-linked ubiquitination of phosphorylated XRCC4, enhancing DNA non-homologous end joining.

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HGNC ID
HGNC:16712
KEGG ID hsa:55294
Full List of the Ferroptosis Target of This Regulator and Corresponding Disease/Drug Response(s)
FBXW7 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).
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Nuclear receptor coactivator 4 (NCOA4) [Driver]
 Target Info 
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
 Disease Info 
Responsed Drug Sorafenib Investigative
 Drug Info 
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.
Voltage-dependent anion-selective channel protein 3 (VDAC3) [Suppressor]
 Target Info 
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [2]
Target for Ferroptosis Suppressor
Responsed Disease Gastric cancer ICD-11: 2B72
 Disease Info 
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
 AGS cells Gastric adenocarcinoma Homo sapiens CVCL_0139
HGC-27 cells Gastric carcinoma Homo sapiens CVCL_1279
BGC-823 cells Gastric carcinoma Homo sapiens CVCL_3360
MGC-803 cells Gastric mucinous adenocarcinoma Homo sapiens CVCL_5334
MKN45 cells Gastric adenocarcinoma Homo sapiens CVCL_0434
GES-1 cells Normal Homo sapiens CVCL_EQ22
In Vivo Model
Four- to six-week-old nude mice (BALB/c) were purchased from Jiangsu Jicui Yaokang Biotechnology Co. Ltd. (Nanjing, China) and then randomly divided into 3 groups (n = 5 per group). PO-BDNF-AS-HGC-27 cells, PONC-BDNF-AS-HGC-27 cells, or PO-BDNF-AS + PO-FBXW7-HGC-27 cells (5 x 106) were suspended in 100 ul DMEM and subcutaneously injected into the flanks of the mice in each group. After 10 days, we measured the tumor size every week using digital Vernier calipers and calculated the tumor volume based on the formula: volume = 1/2 x (width2 x length). On the 30th day or when the tumor became larger than 1.5 cm in diameter, the mice were sacrificed. Subsequently, the subcutaneous graft tumors were removed for further experiments. For the intraabdominal tumor model, we randomly divided the mice into two groups (n = 6 per group). PO-BDNF-AS-HGC-27 cells or PONC-BDNF-AS-HGC-27 cells (8 x 106) were suspended in 150 uL DMEM and intraperitoneally injected into the mice in each group (weight, approximately 18.0-19.0 g). Five weeks after injection, the mice were euthanized and necropsied to assess abdominal tumor burden and tumor location. Finally, we detected the mRNA and protein expression levels of relevant genes in the tumor tissues by RT-PCR and western blotting assays.

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Response regulation BDNF-AS could regulate FBXW7 expression by recruiting WDR5, thus affecting FBXW7 transcription, and FBXW7 regulated the protein expression of VDAC3 through ubiquitination. Conclusively, our research demonstrated that the BDNF-AS/WDR5/FBXW7 axis regulates ferroptosis in gastric cancer by affecting VDAC3 ubiquitination.
Stearoyl-CoA desaturase (SCD) [Suppressor]
 Target Info 
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [3]
Target for Ferroptosis Suppressor
Responsed Disease Pancreatic cancer ICD-11: 2C10
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Apoptosis hsa04210
Cell Process Cell ferroptosis
Cell apoptosis
In Vitro Model
 PANC-1 cells Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0480
SW1990 cells Pancreatic adenocarcinoma Homo sapiens CVCL_1723
Response regulation FBW7 (FBXW7) inhibited the expression of stearoyl-CoA desaturase (SCD1) via inhibiting nuclear receptor subfamily 4 group A member 1 (NR4A1). SCD1 was reported to inhibit both ferroptosis and apoptosis. And activating ferroptosis and apoptosis immensely increased gemcitabine sensitivity, which might provide strategies for the combination therapy for pancreatic cancer.
Liver fibrosis [ICD-11: DB93]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator F-box/WD repeat-containing protein 7 (FBXW7) Protein coding
 Regulator Info 
Responsed Drug Sorafenib Investigative
 Drug Info 
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.
Gastric cancer [ICD-11: 2B72]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [2]
Target Regulator F-box/WD repeat-containing protein 7 (FBXW7) Protein coding
 Regulator Info 
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
 AGS cells Gastric adenocarcinoma Homo sapiens CVCL_0139
HGC-27 cells Gastric carcinoma Homo sapiens CVCL_1279
BGC-823 cells Gastric carcinoma Homo sapiens CVCL_3360
MGC-803 cells Gastric mucinous adenocarcinoma Homo sapiens CVCL_5334
MKN45 cells Gastric adenocarcinoma Homo sapiens CVCL_0434
GES-1 cells Normal Homo sapiens CVCL_EQ22
In Vivo Model
Four- to six-week-old nude mice (BALB/c) were purchased from Jiangsu Jicui Yaokang Biotechnology Co. Ltd. (Nanjing, China) and then randomly divided into 3 groups (n = 5 per group). PO-BDNF-AS-HGC-27 cells, PONC-BDNF-AS-HGC-27 cells, or PO-BDNF-AS + PO-FBXW7-HGC-27 cells (5 x 106) were suspended in 100 ul DMEM and subcutaneously injected into the flanks of the mice in each group. After 10 days, we measured the tumor size every week using digital Vernier calipers and calculated the tumor volume based on the formula: volume = 1/2 x (width2 x length). On the 30th day or when the tumor became larger than 1.5 cm in diameter, the mice were sacrificed. Subsequently, the subcutaneous graft tumors were removed for further experiments. For the intraabdominal tumor model, we randomly divided the mice into two groups (n = 6 per group). PO-BDNF-AS-HGC-27 cells or PONC-BDNF-AS-HGC-27 cells (8 x 106) were suspended in 150 uL DMEM and intraperitoneally injected into the mice in each group (weight, approximately 18.0-19.0 g). Five weeks after injection, the mice were euthanized and necropsied to assess abdominal tumor burden and tumor location. Finally, we detected the mRNA and protein expression levels of relevant genes in the tumor tissues by RT-PCR and western blotting assays.

    Click to Show/Hide
Response regulation BDNF-AS could regulate FBXW7 expression by recruiting WDR5, thus affecting FBXW7 transcription, and FBXW7 regulated the protein expression of VDAC3 through ubiquitination. Conclusively, our research demonstrated that the BDNF-AS/WDR5/FBXW7 axis regulates ferroptosis in gastric cancer by affecting VDAC3 ubiquitination.
Pancreatic cancer [ICD-11: 2C10]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [3]
Target Regulator F-box/WD repeat-containing protein 7 (FBXW7) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Apoptosis hsa04210
Cell Process Cell ferroptosis
Cell apoptosis
In Vitro Model
 PANC-1 cells Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0480
SW1990 cells Pancreatic adenocarcinoma Homo sapiens CVCL_1723
Response regulation FBW7 (FBXW7) inhibited the expression of stearoyl-CoA desaturase (SCD1) via inhibiting nuclear receptor subfamily 4 group A member 1 (NR4A1). SCD1 was reported to inhibit both ferroptosis and apoptosis. And activating ferroptosis and apoptosis immensely increased gemcitabine sensitivity, which might provide strategies for the combination therapy for pancreatic cancer.
Sorafenib [Investigative]
 Drug Info 
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
 Target Info 
Responsed Disease Liver fibrosis ICD-11: DB93
 Disease Info 
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.
Ref 2 The lncRNA BDNF-AS/WDR5/FBXW7 axis mediates ferroptosis in gastric cancer peritoneal metastasis by regulating VDAC3 ubiquitination. Int J Biol Sci. 2022 Jan 24;18(4):1415-1433. doi: 10.7150/ijbs.69454. eCollection 2022.
Ref 3 FBW7-NRA41-SCD1 axis synchronously regulates apoptosis and ferroptosis in pancreatic cancer cells. Redox Biol. 2021 Jan;38:101807. doi: 10.1016/j.redox.2020.101807. Epub 2020 Nov 24.