Molecule Information

General Information of the Molecule (ID: Mol00632)

• Name: Mothers against decapentaplegic homolog 3 (SMAD3) ,Homo sapiens
• Synonyms: MAD homolog 3; Mad3; Mothers against DPP homolog 3; hMAD-3; JV15-2; SMAD family member 3; SMAD 3; Smad3; hSMAD3; MADH3
• Molecule Type: Protein
• Gene Name: SMAD3
• Gene ID: 4088
• Location: chr15:67063763-67195173[+]
• Sequence:
  MSSILPFTPPIVKRLLGWKKGEQNGQEEKWCEKAVKSLVKKLKKTGQLDELEKAITTQNV
  NTKCITIPRSLDGRLQVSHRKGLPHVIYCRLWRWPDLHSHHELRAMELCEFAFNMKKDEV
  CVNPYHYQRVETPVLPPVLVPRHTEIPAEFPPLDDYSHSIPENTNFPAGIEPQSNIPETP
  PPGYLSEDGETSDHQMNHSMDAGSPNLSPNPMSPAHNNLDLQPVTYCEPAFWCSISYYEL
  NQRVGETFHASQPSMTVDGFTDPSNSERFCLGLLSNVNRNAAVELTRRHIGRGVRLYYIG
  GEVFAECLSDSAIFVQSPNCNQRYGWHPATVCKIPPGCNLKIFNNQEFAALLAQSVNQGF
  EAVYQLTRMCTIRMSFVKGWGAEYRRQTVTSTPCWIELHLNGPLQWLDKVLTQMGSPSIR
  CSSVS
• 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.
• Uniprot ID: SMAD3_HUMAN
• Ensembl ID: ENSG00000166949
• HGNC ID: HGNC:6769

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 5 drug(s) in total

Bromocriptine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Disease Class: Prolactinomas [1]

• Resistant Disease: Prolactinomas [ICD-11: 2F37.2]
• Resistant Drug: Bromocriptine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: TGF-beta 1/Smad3 pathway; Activation; hsa04350
• In Vitro Model: HS27 cells; Bone; Homo sapiens (Human); CVCL_0E34
• In Vitro Model: MMQ cells; Pituitary gland; Rattus norvegicus (Rat); CVCL_2117
• Experiment for Molecule Alteration: Western blotting assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: TGF-beta1 promotes the synthesis and secretion of collagen fibers in fibroblasts and that the TGF-beta1/Smad3 pathway is involved in the mechanism of prolactinoma resistance by increasing fibrosis through interactions with fibroblasts.

Doxorubicin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Disease Class: Breast cancer [2]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Sensitive Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-489 was significantly suppressed in MCF-7/ADM cells compared with chemosensitive parental control MCF-7/WT cells. Forced-expression of miR-489 reversed chemoresistance. Furthermore, Smad3 was identified as the target of miR-489 and is highly expressed in MCF-7/ADM cells. Forced expression of miR-489 both inhibited Smad3 expression and Smad3 related EMT properties. Finally, the interactions between Smad3, miR-489 and EMT were confirmed in chemoresistant tumor xenografts and clinical samples, indicating their potential implication for treatment of chemoresistance.

LY2835219

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [3]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: LY2835219
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: Smad3 is a component of the TGF-beta signaling pathway, having antiproliferative effects that contribute to G1 cell cycle arrest. From this perspective, it was demonstrated that the suppression of Smad3 was involved in mechanisms responsible for resistance to certain anticancer drugs, such as trastzumab. Furthermore, some evidences suggested that Smad3 may be correlated with resistance to CDK4/6 inhibitors. Mechanistically, Smad3 was reported to be suppressed through phosphorylation by the cyclin E-CDK2 or cyclin D1-CDK4/6 complexes.

Palbociclib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [3]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: Palbociclib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: Smad3 is a component of the TGF-beta signaling pathway, having antiproliferative effects that contribute to G1 cell cycle arrest. From this perspective, it was demonstrated that the suppression of Smad3 was involved in mechanisms responsible for resistance to certain anticancer drugs, such as trastzumab. Furthermore, some evidences suggested that Smad3 may be correlated with resistance to CDK4/6 inhibitors. Mechanistically, Smad3 was reported to be suppressed through phosphorylation by the cyclin E-CDK2 or cyclin D1-CDK4/6 complexes.

Ribociclib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [3]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: Ribociclib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: Smad3 is a component of the TGF-beta signaling pathway, having antiproliferative effects that contribute to G1 cell cycle arrest. From this perspective, it was demonstrated that the suppression of Smad3 was involved in mechanisms responsible for resistance to certain anticancer drugs, such as trastzumab. Furthermore, some evidences suggested that Smad3 may be correlated with resistance to CDK4/6 inhibitors. Mechanistically, Smad3 was reported to be suppressed through phosphorylation by the cyclin E-CDK2 or cyclin D1-CDK4/6 complexes.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Breast cancer [ICD-11: 2C60]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Breast tissue
• The Specified Disease: Breast cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.40E-28; Fold-change: -3.59E-01; Z-score: -9.53E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 5.65E-06; Fold-change: -3.84E-01; Z-score: -9.76E-01

Pituitary cancer [ICD-11: 2F37]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Pituitary
• The Specified Disease: Pituitary cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.72E-03; Fold-change: -3.51E-01; Z-score: -1.18E+00
• The Studied Tissue: Pituitary
• The Specified Disease: Pituitary gonadotrope tumor
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.57E-02; Fold-change: -5.17E-01; Z-score: -1.41E+00

References

• Ref 1: Role of TGF-Beta1/Smad3-mediated fibrosis in drug resistance mechanism of prolactinoma .Brain Res. 2018 Nov 1;1698:204-212. doi: 10.1016/j.brainres.2018.07.024. Epub 2018 Jul 27. 10.1016/j.brainres.2018.07.024
• Ref 2: MiR-489 regulates chemoresistance in breast cancer via epithelial mesenchymal transition pathway. FEBS Lett. 2014 May 29;588(11):2009-15. doi: 10.1016/j.febslet.2014.04.024. Epub 2014 Apr 29.
• Ref 3: Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: A review .Int J Cancer. 2019 Sep 1;145(5):1179-1188. doi: 10.1002/ijc.32020. Epub 2019 Jan 7. 10.1002/ijc.32020