Ferroptosis Regulator Information

General Information of the Ferroptosis Regulator (ID: REG10337)
Regulator Name Iron-sulfur cluster assembly enzyme ISCU (ISCU)
Synonyms
NIFUN; NifU-like N-terminal domain-containing protein; NifU-like protein
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Gene Name ISCU
Gene ID 23479
Regulator Type Protein coding
Uniprot ID Q9H1K1
Sequence
MAAAGAFRLRRAASALLLRSPRLPARELSAPARLYHKKVVDHYENPRNVGSLDKTSKNVG
TGLVGAPACGDVMKLQIQVDEKGKIVDARFKTFGCGSAIASSSLATEWVKGKTVEEALTI
KNTDIAKELCLPPVKLHCSMLAEDAIKAALADYKLKQEPKKGEAEKK

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Family NifU family
Function
Mitochondrial scaffold protein, of the core iron-sulfur cluster (ISC) assembly complex, that provides the structural architecture on which the [2Fe-2S] clusters are assembled. The core iron-sulfur cluster (ISC) assembly complex is involved in the de novo synthesis of a [2Fe-2S] cluster, the first step of the mitochondrial iron-sulfur protein biogenesis. This process is initiated by the cysteine desulfurase complex (NFS1:LYRM4:NDUFAB1) that produces persulfide which is delivered on the scaffold protein ISCU in a FXN-dependent manner. Then this complex is stabilized by FDX2 which provides reducing equivalents to accomplish the [2Fe-2S] cluster assembly. Finally, the [2Fe-2S] cluster is transferred from ISCU to chaperone proteins, including HSCB, HSPA9 and GLRX5 (Probable). Exists as two slow interchanging conformational states, a structured (S) and disordered (D) form. May modulate NFS1 desulfurase activity in a zinc-dependent manner. Modulates the interaction between FXN and the cysteine desulfurase complex.

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HGNC ID
HGNC:29882
KEGG ID hsa:23479
Full List of the Ferroptosis Target of This Regulator and Corresponding Disease/Drug Response(s)
ISCU 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
Ferritin heavy chain (FTH1) [Suppressor; Marker]
 Target Info 
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Acute myeloid leukaemia ICD-11: 2A60
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
Cell proliferation
Cell cycle
In Vitro Model
 HL-60 cells Adult acute myeloid leukemia Homo sapiens CVCL_0002
KG1 cells Normal Mus musculus CVCL_UD72
THP-1 cells Childhood acute monocytic leukemia Homo sapiens CVCL_0006
In Vivo Model
BALB/c Nude Mice (4 weeks old) were obtained from Shanghai Experimental Animal Center of the Chinese Academy of Sciences (Shanghai, China) and then subcutaneously injection with HL60 cells (1 x 107, suspended in 0.1 mL PBS). After tumors reached 100-200 mm3, the mice were randomly assigned to two groups. DHA was administered intraperitoneal injection once a day at 50 mg/kg body weight and the mice in normal control were received equal amounts of vehicle (10% DMSO in sterile corn oil). On the 28th day, mice were euthanized. The tumor volumes were measured every 4 days with a caliper.

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Response regulation Dihydroartemisinin (DHA) strongly inhibited the viability of acute myeloid leukemia (AML) cell lines and arrest cell cycle at G0/G1 phase. ISCU over-expression robustly alleviated the iron starvation response through regulating the expression of IRPs and downstream FTH. ISCU significantly attenuated DHA induced ferroptosis by regulating iron metabolism, rescuing the mitochondrial function and increasing the level of GSH.
Acute myeloid leukaemia [ICD-11: 2A60]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator Iron-sulfur cluster assembly enzyme ISCU (ISCU) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
Cell proliferation
Cell cycle
In Vitro Model
 HL-60 cells Adult acute myeloid leukemia Homo sapiens CVCL_0002
KG1 cells Normal Mus musculus CVCL_UD72
THP-1 cells Childhood acute monocytic leukemia Homo sapiens CVCL_0006
In Vivo Model
BALB/c Nude Mice (4 weeks old) were obtained from Shanghai Experimental Animal Center of the Chinese Academy of Sciences (Shanghai, China) and then subcutaneously injection with HL60 cells (1 x 107, suspended in 0.1 mL PBS). After tumors reached 100-200 mm3, the mice were randomly assigned to two groups. DHA was administered intraperitoneal injection once a day at 50 mg/kg body weight and the mice in normal control were received equal amounts of vehicle (10% DMSO in sterile corn oil). On the 28th day, mice were euthanized. The tumor volumes were measured every 4 days with a caliper.

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Response regulation Dihydroartemisinin (DHA) strongly inhibited the viability of acute myeloid leukemia (AML) cell lines and arrest cell cycle at G0/G1 phase. ISCU over-expression robustly alleviated the iron starvation response through regulating the expression of IRPs and downstream FTH. ISCU significantly attenuated DHA induced ferroptosis by regulating iron metabolism, rescuing the mitochondrial function and increasing the level of GSH.
References
Ref 1 DHA inhibits proliferation and induces ferroptosis of leukemia cells through autophagy dependent degradation of ferritin. Free Radic Biol Med. 2019 Feb 1;131:356-369. doi: 10.1016/j.freeradbiomed.2018.12.011. Epub 2018 Dec 14.