Ferroptosis Regulator Information

General Information of the Ferroptosis Regulator (ID: REG10100)
Regulator Name Cyclic AMP-dependent transcription factor ATF-2 (ATF2)
Synonyms
CREB2, CREBP1; Activating transcription factor 2; Cyclic AMP-responsive element-binding protein 2; HB16; cAMP response element-binding protein CRE-BP1
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Gene Name ATF2
Gene ID 1386
Regulator Type Protein coding
Uniprot ID P15336
Sequence
MKFKLHVNSARQYKDLWNMSDDKPFLCTAPGCGQRFTNEDHLAVHKHKHEMTLKFGPARN
DSVIVADQTPTPTRFLKNCEEVGLFNELASPFENEFKKASEDDIKKMPLDLSPLATPIIR
SKIEEPSVVETTHQDSPLPHPESTTSDEKEVPLAQTAQPTSAIVRPASLQVPNVLLTSSD
SSVIIQQAVPSPTSSTVITQAPSSNRPIVPVPGPFPLLLHLPNGQTMPVAIPASITSSNV
HVPAAVPLVRPVTMVPSVPGIPGPSSPQPVQSEAKMRLKAALTQQHPPVTNGDTVKGHGS
GLVRTQSEESRPQSLQQPATSTTETPASPAHTTPQTQSTSGRRRRAANEDPDEKRRKFLE
RNRAAASRCRQKRKVWVQSLEKKAEDLSSLNGQLQSEVTLLRNEVAQLKQLLLAHKDCPV
TAMQKKSGYHTADKDDSSEDISVPSSPHTEAIQHSSVSTSNGVSSTSKAEAVATSVLTQM
ADQSTEPALSQIVMAPSSQSQPSGS

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Family BZIP family
Function
Transcriptional activator which regulates the transcription of various genes, including those involved in anti-apoptosis, cell growth, and DNA damage response. Dependent on its binding partner, binds to CRE (cAMP response element) consensus sequences (5'-TGACGTCA- 3') or to AP-1 (activator protein 1) consensus sequences (5'-TGACTCA- 3'). In the nucleus, contributes to global transcription and the DNA damage response, in addition to specific transcriptional activities that are related to cell development, proliferation and death. In the cytoplasm, interacts with and perturbs HK1- and VDAC1-containing complexes at the mitochondrial outer membrane, thereby impairing mitochondrial membrane potential, inducing mitochondrial leakage and promoting cell death. The phosphorylated form (mediated by ATM) plays a role in the DNA damage response and is involved in the ionizing radiation (IR)-induced S phase checkpoint control and in the recruitment of the MRN complex into the IR-induced foci (IRIF). Exhibits histone acetyltransferase (HAT) activity which specifically acetylates histones H2B and H4 in vitro. In concert with CUL3 and RBX1, promotes the degradation of KAT5 thereby attenuating its ability to acetylate and activate ATM. Can elicit oncogenic or tumor suppressor activities depending on the tissue or cell type.

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HGNC ID
HGNC:784
KEGG ID hsa:1386
Full List of the Ferroptosis Target of This Regulator and Corresponding Disease/Drug Response(s)
ATF2 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
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Unspecific Target [Unspecific Target]
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Responsed Disease Gastric cancer ICD-11: 2B72
 Disease Info 
Responsed Drug Amentoflavone Investigative
 Drug Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 GSE-1 (Human gastric mucosal epithelial cells)
AGS cells Gastric adenocarcinoma Homo sapiens CVCL_0139
HGC-27 cells Gastric carcinoma Homo sapiens CVCL_1279
In Vivo Model
The BALB/c nude mice (n = 15, 4-6 weeks old) were purchased from Charles River Labs and kept under controlled conditions. Then 1 x 106 AGS cells were inoculated subcutaneously into nude mice. When the tumor reached to 100 mm3, mice were randomly divided into three groups, the control group was intraperitoneally injected with saline, the AF group was intraperitoneally injected with AF at dosages of 80 mg/kg/day, and AF + anti-miR-496 group received intraperitoneal injection, followed by the administration of miR-496 antagonist via intra-tumor injection once a week for 4 weeks.

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Response regulation Amentoflavone suppressed the proliferation and induced ferroptotic cell death in gastric cancer cells via miR-496/ATF2 axis, indicating a novel therapeutic approach for GC patients.
Nuclear factor erythroid 2-related factor 2 (NFE2L2) [Suppressor; Marker]
 Target Info 
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [2]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Breast cancer ICD-11: 2C60
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
 MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
BT-549 cells Invasive breast carcinoma Homo sapiens CVCL_1092
HeLa cells Endocervical adenocarcinoma Homo sapiens CVCL_0030
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
In Vivo Model
Athymic nu/nu mice (5 to 6-week-old female) were acquired from the Silaike Experimental Animal Co. Ltd (Shanghai, China). Mice was randomly divided into different groups (n = 6 per group), 1 x 106 MB-231 cells with stable overexpression of ATF2 and control cells were subcutaneously inoculated on the right flanks. Seven days later, mice were injected intraperitoneally with PBS containingdimethyl sulfoxide(DMSO) and JQ1 (50 mg/kg) once every 2-4 days for 8 times, and the tumor volumes and body weight of mice were monitored and recorded every 23 days.

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Response regulation ATF2 inhibited BETi-induced ferroptosis by increasing NRF2 expression. Altogether, ATF2 suppressed ani-tumor effects of BETi in a negative feedback manner by attenuating ferroptosis. BETi combined with ATF2 or NRF2 inhibitor might be a novel strategy for treatment of Breast cancer.
Cystine/glutamate transporter (SLC7A11) [Driver; 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 Gastric cancer ICD-11: 2B72
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 GES-1 cells Normal Homo sapiens CVCL_EQ22
SGC-7901 cells Gastric carcinoma Homo sapiens CVCL_0520
HGC-27 cells Gastric carcinoma Homo sapiens CVCL_1279
AGS cells Gastric adenocarcinoma Homo sapiens CVCL_0139
MGC-803 cells Gastric mucinous adenocarcinoma Homo sapiens CVCL_5334
MKN45 cells Gastric adenocarcinoma Homo sapiens CVCL_0434
In Vivo Model
Four-week-old female BALB/c nude mice were purchased from SLAC Laboratory Animal Co., Ltd. (Shanghai, China). For subsequent studies, the nude mice were randomly divided into four groups as follows: sh-Ctrl, sh-ATF2, sh-Ctrl + sorafenib and sh-ATF2 + sorafenib. Approximately 5 x 106 ATF2 knockdown or control MGC803 cells were subcutaneously injected into the axilla of nude mice. Beginning on Day 8, mice in the sorafenib treatment group received 10 mg/kg sorafenib by intraperitoneal injection every 2 days for 3 weeks.

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Response regulation Using ChIP-Seq and RNA-Seq, HSPH1 as a target of ATF2 and further validated it by ChIPqPCR analysis. HSPH1 can interact with SLC7A11 (cystine/glutamate transporter) and increase its protein stability. Importantly, knockdown of HSPH1 partly reversed the effects caused by ATF2 overexpression on sorafenib-induced ferroptosis in gastric cancer cells.
Gastric cancer [ICD-11: 2B72]
 Disease Info 
In total 2 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator Cyclic AMP-dependent transcription factor ATF-2 (ATF2) Protein coding
 Regulator Info 
Responsed Drug Amentoflavone Investigative
 Drug Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 GSE-1 (Human gastric mucosal epithelial cells)
AGS cells Gastric adenocarcinoma Homo sapiens CVCL_0139
HGC-27 cells Gastric carcinoma Homo sapiens CVCL_1279
In Vivo Model
The BALB/c nude mice (n = 15, 4-6 weeks old) were purchased from Charles River Labs and kept under controlled conditions. Then 1 x 106 AGS cells were inoculated subcutaneously into nude mice. When the tumor reached to 100 mm3, mice were randomly divided into three groups, the control group was intraperitoneally injected with saline, the AF group was intraperitoneally injected with AF at dosages of 80 mg/kg/day, and AF + anti-miR-496 group received intraperitoneal injection, followed by the administration of miR-496 antagonist via intra-tumor injection once a week for 4 weeks.

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Response regulation Amentoflavone suppressed the proliferation and induced ferroptotic cell death in gastric cancer cells via miR-496/ATF2 axis, indicating a novel therapeutic approach for GC patients.
Experiment 2 Reporting the Ferroptosis-centered Disease Response [3]
Target Regulator Cyclic AMP-dependent transcription factor ATF-2 (ATF2) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 GES-1 cells Normal Homo sapiens CVCL_EQ22
SGC-7901 cells Gastric carcinoma Homo sapiens CVCL_0520
HGC-27 cells Gastric carcinoma Homo sapiens CVCL_1279
AGS cells Gastric adenocarcinoma Homo sapiens CVCL_0139
MGC-803 cells Gastric mucinous adenocarcinoma Homo sapiens CVCL_5334
MKN45 cells Gastric adenocarcinoma Homo sapiens CVCL_0434
In Vivo Model
Four-week-old female BALB/c nude mice were purchased from SLAC Laboratory Animal Co., Ltd. (Shanghai, China). For subsequent studies, the nude mice were randomly divided into four groups as follows: sh-Ctrl, sh-ATF2, sh-Ctrl + sorafenib and sh-ATF2 + sorafenib. Approximately 5 x 106 ATF2 knockdown or control MGC803 cells were subcutaneously injected into the axilla of nude mice. Beginning on Day 8, mice in the sorafenib treatment group received 10 mg/kg sorafenib by intraperitoneal injection every 2 days for 3 weeks.

    Click to Show/Hide
Response regulation Using ChIP-Seq and RNA-Seq, HSPH1 as a target of ATF2 and further validated it by ChIPqPCR analysis. HSPH1 can interact with SLC7A11 (cystine/glutamate transporter) and increase its protein stability. Importantly, knockdown of HSPH1 partly reversed the effects caused by ATF2 overexpression on sorafenib-induced ferroptosis in gastric cancer cells.
Breast cancer [ICD-11: 2C60]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [2]
Target Regulator Cyclic AMP-dependent transcription factor ATF-2 (ATF2) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
 MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
BT-549 cells Invasive breast carcinoma Homo sapiens CVCL_1092
HeLa cells Endocervical adenocarcinoma Homo sapiens CVCL_0030
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
In Vivo Model
Athymic nu/nu mice (5 to 6-week-old female) were acquired from the Silaike Experimental Animal Co. Ltd (Shanghai, China). Mice was randomly divided into different groups (n = 6 per group), 1 x 106 MB-231 cells with stable overexpression of ATF2 and control cells were subcutaneously inoculated on the right flanks. Seven days later, mice were injected intraperitoneally with PBS containingdimethyl sulfoxide(DMSO) and JQ1 (50 mg/kg) once every 2-4 days for 8 times, and the tumor volumes and body weight of mice were monitored and recorded every 23 days.

    Click to Show/Hide
Response regulation ATF2 inhibited BETi-induced ferroptosis by increasing NRF2 expression. Altogether, ATF2 suppressed ani-tumor effects of BETi in a negative feedback manner by attenuating ferroptosis. BETi combined with ATF2 or NRF2 inhibitor might be a novel strategy for treatment of Breast cancer.
Amentoflavone [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 Unspecific Target
Responsed Disease Gastric cancer ICD-11: 2B72
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 GSE-1 (Human gastric mucosal epithelial cells)
AGS cells Gastric adenocarcinoma Homo sapiens CVCL_0139
HGC-27 cells Gastric carcinoma Homo sapiens CVCL_1279
In Vivo Model
The BALB/c nude mice (n = 15, 4-6 weeks old) were purchased from Charles River Labs and kept under controlled conditions. Then 1 x 106 AGS cells were inoculated subcutaneously into nude mice. When the tumor reached to 100 mm3, mice were randomly divided into three groups, the control group was intraperitoneally injected with saline, the AF group was intraperitoneally injected with AF at dosages of 80 mg/kg/day, and AF + anti-miR-496 group received intraperitoneal injection, followed by the administration of miR-496 antagonist via intra-tumor injection once a week for 4 weeks.

    Click to Show/Hide
Response regulation Amentoflavone suppressed the proliferation and induced ferroptotic cell death in gastric cancer cells via miR-496/ATF2 axis, indicating a novel therapeutic approach for GC patients.
References
Ref 1 Amentoflavone attenuates cell proliferation and induces ferroptosis in human gastric cancer by miR-496/ATF2 axis. Chem Biol Drug Des. 2023 Oct;102(4):782-792. doi: 10.1111/cbdd.14288. Epub 2023 Jul 16.
Ref 2 ATF2 inhibits ani-tumor effects of BET inhibitor in a negative feedback manner by attenuating ferroptosis. Biochem Biophys Res Commun. 2021 Jun 18;558:216-223. doi: 10.1016/j.bbrc.2020.08.113. Epub 2020 Sep 30.
Ref 3 Increased ATF2 expression predicts poor prognosis and inhibits sorafenib-induced ferroptosis in gastric cancer. Redox Biol. 2023 Feb;59:102564. doi: 10.1016/j.redox.2022.102564. Epub 2022 Dec 2.