m6A Target Gene Information

General Information of the m6A Target Gene (ID: M6ATAR00396)
Target Name Mothers against decapentaplegic homolog 3 (SMAD3)
Synonyms
MAD homolog 3; Mad3; Mothers against DPP homolog 3; hMAD-3; JV15-2; SMAD family member 3; SMAD 3; Smad3; hSMAD3; MADH3
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Gene Name SMAD3
Chromosomal Location 15q22.33
Family dwarfin/SMAD family
Function
Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases. Binds the TRE element in the promoter region of many genes that are regulated by TGF-beta and, on formation of the SMAD3/SMAD4 complex, activates transcription. Also can form a SMAD3/SMAD4/JUN/FOS complex at the AP-1/SMAD site to regulate TGF-beta-mediated transcription. Has an inhibitory effect on wound healing probably by modulating both growth and migration of primary keratinocytes and by altering the TGF-mediated chemotaxis of monocytes. This effect on wound healing appears to be hormone-sensitive. Regulator of chondrogenesis and osteogenesis and inhibits early healing of bone fractures. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.
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Gene ID 4088
Uniprot ID
SMAD3_HUMAN
HGNC ID
HGNC:6769
Ensembl Gene ID
ENSG00000166949
KEGG ID
hsa:4088
Full List of m6A Methylation Regulator of This Target Gene and Corresponding Disease/Drug Response(s)
SMAD3 can be regulated by the following regulator(s), and cause disease/drug response(s). You can browse detail information of regulator(s) or disease/drug response(s).
Browse Regulator
Browse Disease
YTH domain-containing family protein 2 (YTHDF2) [READER]
 Regulator Info 
Representative RNA-seq result indicating the expression of this target gene regulated by YTHDF2
Cell Line mouse embryonic stem cells Mus musculus
Treatment: shYthdf2 embryonic stem cells
Control: shLuc embryonic stem cells
 GSE156437
Regulation
logFC: 5.96E-01
p-value: 6.99E-03
More Results Click to View More RNA-seq Results
Representative RIP-seq result supporting the interaction between SMAD3 and the regulator
Cell Line Hela Homo sapiens
Regulation logFC: 1.21E+00 GSE49339
In total 1 item(s) under this regulator
Experiment 1 Reporting the m6A Methylation Regulator of This Target Gene [1]
Response Summary YTHDF2 inhibits the migration and invasion of lung adenocarcinoma cells by regulating the FAM83D-TGFbeta1-Mothers against decapentaplegic homolog 3 (SMAD3) pathway, which will play an important role in lung cancer metastasis.
Target Regulation Down regulation
Responsed Disease Lung cancer ICD-11: 2C25
 Disease Info 
Pathway Response mRNA surveillance pathway hsa03015
Cell Process Epithelial-mesenchymal transition
In-vitro Model NCI-H1299 Lung large cell carcinoma Homo sapiens CVCL_0060
A-549 Lung adenocarcinoma Homo sapiens CVCL_0023
Methyltransferase-like 3 (METTL3) [WRITER]
 Regulator Info 
Representative RNA-seq result indicating the expression of this target gene regulated by METTL3
Cell Line mouse embryonic stem cells Mus musculus
Treatment: METTL3-/- ESCs
Control: Wild type ESCs
 GSE145309
Regulation
logFC: 1.25E+00
p-value: 1.46E-105
More Results Click to View More RNA-seq Results
In total 1 item(s) under this regulator
Experiment 1 Reporting the m6A Methylation Regulator of This Target Gene [2]
Response Summary METTL3-induced circ1662 promoted colorectal cancer cell invasion and migration by accelerating YAP1 nuclear transport. Circ1662 enhanced CRC invasion and migration depending on YAP1 and Mothers against decapentaplegic homolog 3 (SMAD3). This result implies that circ1662 is a new prognostic and therapeutic marker for CRC metastasis.
Target Regulation Down regulation
Responsed Disease Colorectal cancer ICD-11: 2B91
 Disease Info 
Pathway Response Hippo signaling pathway hsa04390
Cell Process Cell invasion
Cell migration
In-vitro Model HEK293T Normal Homo sapiens CVCL_0063
HCT 116 Colon carcinoma Homo sapiens CVCL_0291
SW480 Colon adenocarcinoma Homo sapiens CVCL_0546
In-vivo Model BALB/c nude mice (4 weeks old) were acquired from Vital River Laboratory (Beijing, China). HCT116 cells with stable circ1662 expression (2 × 106 in 100 L of PBS) were injected via the tail vein. After 45 days, the mice were sacrificed. The lung metastatic carcinoma specimens were processed into paraffin-embedded sections for subsequent H&E staining and IHC.
RNA demethylase ALKBH5 (ALKBH5) [ERASER]
 Regulator Info 
Representative RNA-seq result indicating the expression of this target gene regulated by ALKBH5
Cell Line MOLM-13 cell line Homo sapiens
Treatment: shALKBH5 MOLM-13 cells
Control: shNS MOLM-13 cells
 GSE144968
Regulation
logFC: 1.59E+00
p-value: 2.50E-03
More Results Click to View More RNA-seq Results
In total 1 item(s) under this regulator
Experiment 1 Reporting the m6A Methylation Regulator of This Target Gene [3]
Response Summary ALKBH5 weakens YTHDF1/3-mediated TGF-Beta-R2 and Mothers against decapentaplegic homolog 3 (SMAD3) mRNA stabilization, and abolishes YTHDF2-mediated SMAD6 mRNA degradation, supporting the notion that ALKBH5 inhibits TGF-Beta-induced EMT and invasion of NSCLC cells via YTHD1/2/3-mediated mechanism.
Target Regulation Down regulation
Responsed Disease Non-small-cell lung carcinoma ICD-11: 2C25.Y
 Disease Info 
Pathway Response TGF-beta signaling pathway hsa04350
Cell Process Epithelial-mesenchymal transition
In-vitro Model HEK293T Normal Homo sapiens CVCL_0063
NCI-H1650 Minimally invasive lung adenocarcinoma Homo sapiens CVCL_1483
A-549 Lung adenocarcinoma Homo sapiens CVCL_0023
In-vivo Model The mice were divided into control group and ALKBH5-overexpressing group (9 mice per group). ALKBH5-overexpressing and control A549 cells (3 × 106 cells/mouse) in 200 uL PBS were intravenously (i.v.) injected into the lateral tail vein of mice. At every 5th day post-inoculation, TGF-Beta-1 (4 ug/kg body weight) was intraperitoneally (i.p.) injected to promote tumor cell metastasis. Eight weeks later, the mice were euthanized, and then their lungs and livers were taken out and fixed in Bouin's solution (Sigma Aldrich, HT101128) or 4% Paraformaldehyde (Beyotime, p0099, Shanghai, China) for macroscopically metastatic nodule analysis.
ETS-related transcription factor Elf-3 (ELF3) [WRITER]
 Regulator Info 
In total 1 item(s) under this regulator
Experiment 1 Reporting the m6A Methylation Regulator of This Target Gene [4]
Response Summary Elf3 plays an important role in the process of phenotypic alterations of podocyte induced by the activation of TGF-beta signals. Elf3 protein levels in patients with DN (R2 = 0.7259) were useful as an early non-invasive marker for podocyte injuries in DN. The epithelium-specific transcription factor, Elf3 was induced by AGE stimulation and, subsequently, upregulated RII expression in cultured podocytes. Induction of Elf3 and activation of RII-Mothers against decapentaplegic homolog 3 (SMAD3) signaling, leading to a decrease in WT1 expression, were observed in podocytes in diabetic human kidneys.
Responsed Disease Chronic kidney disease ICD-11: GB61.Z
 Disease Info 
Pathway Response TGF-beta signaling pathway hsa04350
In-vitro Model Murine podocytes Normal Mus musculus CVCL_5737
In-vivo Model In the present study, we assessed Smad3 +/- mice for a comparatively long period to examine the effects of Smad3 expression and phosphorylation and to evaluate the involvement of Smad3 in DN. Heterozygous Smad3- knockout mice were kindly provided by Dr. Yasue, University of Tokushima. We attempted to generate Smad3-null mice using pairs of Smad3 mice, but progeny was rarely obtained, and pups were fragile and could not survive for a long period (5 weeks at the most). Therefore, BKS/Cg-m Lepr db (db/db) x Smad3 +/- mice were developed using pairs of Lepr db +/- x Smad3 +/-. Smad3 +/-;db/+ mice were generated by crossing Smad3 +/- and db/+ mice. Moreover, Smad3 +/-;db/db were generated by crossing Smad3 +/-;db/+ and db/+ mice as previously described. Blood glucose concentrations were measured from the tail vein (glucose assay kit; Abbott). The diabetic phenotype was confirmed 4 weeks after birth by blood glucose >300 mg/dl.
Colorectal cancer [ICD-11: 2B91]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the m6A-centered Disease Response [2]
Response Summary METTL3-induced circ1662 promoted colorectal cancer cell invasion and migration by accelerating YAP1 nuclear transport. Circ1662 enhanced CRC invasion and migration depending on YAP1 and Mothers against decapentaplegic homolog 3 (SMAD3). This result implies that circ1662 is a new prognostic and therapeutic marker for CRC metastasis.
Responsed Disease Colorectal cancer [ICD-11: 2B91]
Target Regulator Methyltransferase-like 3 (METTL3) WRITER
 Regulator Info 
Target Regulation Down regulation
Pathway Response Hippo signaling pathway hsa04390
Cell Process Cell invasion
Cell migration
In-vitro Model HEK293T Normal Homo sapiens CVCL_0063
HCT 116 Colon carcinoma Homo sapiens CVCL_0291
SW480 Colon adenocarcinoma Homo sapiens CVCL_0546
In-vivo Model BALB/c nude mice (4 weeks old) were acquired from Vital River Laboratory (Beijing, China). HCT116 cells with stable circ1662 expression (2 × 106 in 100 L of PBS) were injected via the tail vein. After 45 days, the mice were sacrificed. The lung metastatic carcinoma specimens were processed into paraffin-embedded sections for subsequent H&E staining and IHC.
Lung cancer [ICD-11: 2C25]
 Disease Info 
In total 2 item(s) under this disease
Experiment 1 Reporting the m6A-centered Disease Response [3]
Response Summary ALKBH5 weakens YTHDF1/3-mediated TGF-Beta-R2 and Mothers against decapentaplegic homolog 3 (SMAD3) mRNA stabilization, and abolishes YTHDF2-mediated SMAD6 mRNA degradation, supporting the notion that ALKBH5 inhibits TGF-Beta-induced EMT and invasion of NSCLC cells via YTHD1/2/3-mediated mechanism.
Responsed Disease Non-small-cell lung carcinoma [ICD-11: 2C25.Y]
Target Regulator RNA demethylase ALKBH5 (ALKBH5) ERASER
 Regulator Info 
Target Regulation Down regulation
Pathway Response TGF-beta signaling pathway hsa04350
Cell Process Epithelial-mesenchymal transition
In-vitro Model HEK293T Normal Homo sapiens CVCL_0063
NCI-H1650 Minimally invasive lung adenocarcinoma Homo sapiens CVCL_1483
A-549 Lung adenocarcinoma Homo sapiens CVCL_0023
In-vivo Model The mice were divided into control group and ALKBH5-overexpressing group (9 mice per group). ALKBH5-overexpressing and control A549 cells (3 × 106 cells/mouse) in 200 uL PBS were intravenously (i.v.) injected into the lateral tail vein of mice. At every 5th day post-inoculation, TGF-Beta-1 (4 ug/kg body weight) was intraperitoneally (i.p.) injected to promote tumor cell metastasis. Eight weeks later, the mice were euthanized, and then their lungs and livers were taken out and fixed in Bouin's solution (Sigma Aldrich, HT101128) or 4% Paraformaldehyde (Beyotime, p0099, Shanghai, China) for macroscopically metastatic nodule analysis.
Experiment 2 Reporting the m6A-centered Disease Response [1]
Response Summary YTHDF2 inhibits the migration and invasion of lung adenocarcinoma cells by regulating the FAM83D-TGFbeta1-Mothers against decapentaplegic homolog 3 (SMAD3) pathway, which will play an important role in lung cancer metastasis.
Responsed Disease Lung cancer [ICD-11: 2C25]
Target Regulator YTH domain-containing family protein 2 (YTHDF2) READER
 Regulator Info 
Target Regulation Down regulation
Pathway Response mRNA surveillance pathway hsa03015
Cell Process Epithelial-mesenchymal transition
In-vitro Model NCI-H1299 Lung large cell carcinoma Homo sapiens CVCL_0060
A-549 Lung adenocarcinoma Homo sapiens CVCL_0023
Chronic kidney disease [ICD-11: GB61]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the m6A-centered Disease Response [4]
Response Summary Elf3 plays an important role in the process of phenotypic alterations of podocyte induced by the activation of TGF-beta signals. Elf3 protein levels in patients with DN (R2 = 0.7259) were useful as an early non-invasive marker for podocyte injuries in DN. The epithelium-specific transcription factor, Elf3 was induced by AGE stimulation and, subsequently, upregulated RII expression in cultured podocytes. Induction of Elf3 and activation of RII-Mothers against decapentaplegic homolog 3 (SMAD3) signaling, leading to a decrease in WT1 expression, were observed in podocytes in diabetic human kidneys.
Responsed Disease Chronic kidney disease [ICD-11: GB61.Z]
Target Regulator ETS-related transcription factor Elf-3 (ELF3) WRITER
 Regulator Info 
Pathway Response TGF-beta signaling pathway hsa04350
In-vitro Model Murine podocytes Normal Mus musculus CVCL_5737
In-vivo Model In the present study, we assessed Smad3 +/- mice for a comparatively long period to examine the effects of Smad3 expression and phosphorylation and to evaluate the involvement of Smad3 in DN. Heterozygous Smad3- knockout mice were kindly provided by Dr. Yasue, University of Tokushima. We attempted to generate Smad3-null mice using pairs of Smad3 mice, but progeny was rarely obtained, and pups were fragile and could not survive for a long period (5 weeks at the most). Therefore, BKS/Cg-m Lepr db (db/db) x Smad3 +/- mice were developed using pairs of Lepr db +/- x Smad3 +/-. Smad3 +/-;db/+ mice were generated by crossing Smad3 +/- and db/+ mice. Moreover, Smad3 +/-;db/db were generated by crossing Smad3 +/-;db/+ and db/+ mice as previously described. Blood glucose concentrations were measured from the tail vein (glucose assay kit; Abbott). The diabetic phenotype was confirmed 4 weeks after birth by blood glucose >300 mg/dl.
References
Ref 1 YTHDF2 Inhibits the Migration and Invasion of Lung Adenocarcinoma by Negatively Regulating the FAM83D-TGFBeta1-SMAD2/3 Pathway. Front Oncol. 2022 Feb 2;12:763341. doi: 10.3389/fonc.2022.763341. eCollection 2022.
Ref 2 N6-methyladenosine-induced circ1662 promotes metastasis of colorectal cancer by accelerating YAP1 nuclear localization. Theranostics. 2021 Feb 25;11(9):4298-4315. doi: 10.7150/thno.51342. eCollection 2021.
Ref 3 RNA demethylase ALKBH5 inhibits TGF-Beta-induced EMT by regulating TGF-Beta/SMAD signaling in non-small cell lung?cancer. FASEB J. 2022 May;36(5):e22283. doi: 10.1096/fj.202200005RR.
Ref 4 Involvement of Elf3 on Smad3 activation-dependent injuries in podocytes and excretion of urinary exosome in diabetic nephropathy. PLoS One. 2019 May 31;14(5):e0216788. doi: 10.1371/journal.pone.0216788. eCollection 2019.