SMAD6

Last update 08 May 2025

Basic Info

Synonyms

hSMAD6, HsT17432, MAD homolog 6

+ [7]

Introduction

Transforming growth factor-beta superfamily receptors signaling occurs through the Smad family of intracellular mediators. SMAD6 is an inhibitory Smad (i-Smad) that negatively regulates signaling downstream of type I transforming growth factor-beta (PubMed:10647776, PubMed:10708948, PubMed:10708949, PubMed:16951688, PubMed:22275001, PubMed:30848080, PubMed:9436979, PubMed:9759503). Acts as a mediator of TGF-beta and BMP anti-inflammatory activities. Suppresses IL1R-TLR signaling through its direct interaction with PEL1, preventing NF-kappa-B activation, nuclear transport and NF-kappa-B-mediated expression of pro-inflammatory genes (PubMed:16951688). Blocks the BMP-SMAD1 signaling pathway by competing with SMAD4 for receptor-activated SMAD1-binding (PubMed:30848080, PubMed:9436979). Binds to regulatory elements in target promoter regions (PubMed:16491121).

100 Clinical Results associated with SMAD6

100 Translational Medicine associated with SMAD6

0 Patents (Medical) associated with SMAD6

609

Literatures (Medical) associated with SMAD6

01 Dec 2025·Molecular Biology Reports

Suppression of chemically induced mammary cancer by early-life oral administration of cholera toxin in mice is associated with aberrant regulation of Bmp and Notch signaling pathways

Article

Author: Afaloniati, Hara ; Markaki, Maria P ; Karagiannis, George S ; Argyris, Dimitrios G ; Poutahidis, Theofilos ; Angelopoulou, Katerina

BACKGROUNDLately, significant attention has been drawn towards the potential efficacy of cholera toxin (CT)-an exotoxin produced by the small intestine pathogenic bacterium Vibrio cholera-in modulating cancer-promoting events. In a recent study, we demonstrated that early-life oral administration of non-pathogenic doses of CT in mice suppressed chemically-induced carcinogenesis in tissues distantly located from the gut. In the mammary gland, CT pretreatment was shown to reduce tumor multiplicity, increase apoptosis and alter the expression of several cancer-related molecules. In the present work we investigated the protumorigenic mammary microenvironment for possible associations between early life CT administration and the expression of key components of the Bmp and Notch signaling pathways.METHODS AND RESULTSTotal RNA from mammary tissue samples were retrieved from a recent experiment where FVB/N female mice were preconditioned with CT and later treated with the carcinogen 7,12-dimethylbenzanthracene (DMBA). Real-time PCR was used for relative quantification of gene expression. Our results revealed that CT anti-tumor effects significantly correlated with deregulation of crucial BMP pathway elements, with downregulation of Bmp7 ligand and upregulation of inhibitory Smad6 being the most prominent alterations observed. Concerning Notch signaling pathway, significantly elevated gene expression levels in the CT-treated DMBA mice, as compared to their non-treated counterparts, were also identified at the ligand-receptor level.CONCLUSIONSThese findings suggest that CT tumor protective effects in the mammary gland are associated with discerning deregulation of components of both Bmp and Notch signaling pathways and provide insights into the mechanisms underlying CT's anti-cancer outcome.

01 Apr 2025·Environment International

PPARγ-SMAD6 axis-mediated inhibition of osteogenic differentiation is involved in BPS-induced osteoporosis

Article

Author: Gu, Aihua ; Zhang, Hongchao ; Zhang, Zhen ; Chen, Yanlong ; Chen, Xiu ; Fu, Zuqiang ; Xu, Jin ; Weng, Zhenkun ; Jiao, Jian ; Hou, Qingzhi ; Li, Jiong ; Liu, Qian ; Jiang, Zhaoyan ; Meng, Sining ; Wang, Shourui ; Wang, Dongmei

Bisphenol S (BPS) is extensively utilized in personal care products, foods, and paper products, raising growing concerns about its potential environmental hazards. However, few studies have reported the effects of BPS exposure on bone homeostasis. In this study, using data from the National Health and Nutrition Examination Survey, we found a negative correlation between urinary BPS and bone mineral density (BMD). To further investigate the underlying mechanisms, C57BL/6 mice were exposed to a human-equivalent dose of BPS for 6 months. Micro-CT analysis demonstrated reduced femoral BMD in the mice, indicating that osteoporosis was caused by chronic exposure. RNA-seq analysis showed that BPS activated PPARγ in human primary mesenchymal stem cells (MSCs). Additionally, 3D molecular docking confirmed a direct interaction between BPS and PPARγ. Bioinformatics analysis identified SMAD6 as a downstream target of PPARγ. Mechanistically, the BPS-PPARγ interaction activated PPARγ, promoting SMAD6 transcription, which inhibited the osteogenic differentiation of MSCs. High-throughput virtual screening further revealed that olodanrigan effectively blocked the BPS-PPARγ interaction, and in vitro assays revealed that olodanrigan blocked the inhibition of osteogenic differentiation of MSCs induced by BPS. Additionally, olodanrigan supplementation inhibited PPARγ levels, thereby reversing BPS-induced osteoporosis. In summary, this study elucidates the role of the PPARγ-SMAD6 axis in mediating BPS-induced osteoporosis and highlights olodanrigan as a promising therapeutic intervention, offering new insights into the health risks posed by BPS and potential targets for treatment.

01 Mar 2025·Journal of Neurosurgery: Pediatrics

Overlap of genetic factors among craniosynostosis and autism spectrum disorder: the presence of autistic cases without craniosynostosis in carriers of shared variants

Article

Author: Sakuma, Mayuko ; Hirota, Tomoya ; Ijichi, Naomi ; Yokoyama, Daisuke ; King, Bryan H. ; Ijichi, Shinji ; Hayashi, Tsuneari

OBJECTIVEA significant overlap of the risk genes respectively listed for craniosynostosis and autism was recently demonstrated in each case series. The purposes of this article were to review the clinical manifestations systemically in previously reported individual cases with the shared variants and to confirm the pleiotropic associations between genotype and phenotype.METHODSThe risk genes or loci were retrieved from the PubMed database (last searched March 2024) as genetic factors for which genotype-phenotype associations were reported in at least 2 different individuals. Clinical details were reviewed in cases with shared genetic factors between craniosynostosis and autism spectrum disorder. In the genotype-phenotype association of syndromic craniosynostosis genes, both syndromic involvement of autistic traits and nonsyndromic autism cases with nonsyndromic variants in the flanking regions of the syndromic mutations were included.RESULTSNonsyndromic craniosynostosis and autism are both underpinned by complex polygenic networks that include multiple risk genes or loci, and a considerable part of the networks might overlap. Although nonsyndromic mild trigonocephaly and autism might be closely associated in carriers of the shared variants, the presence of cases with autism without mild trigonocephaly was confirmed in a PJA1 variant case. As one of the characteristics of epistasis, ethnic specificity has been demonstrated in the interactions between SMAD6 and BMP2 variants. The presence of autism cases without craniosynostosis on a shared genetic basis was also confirmed in syndromic craniosynostosis risk genes and loci, suggesting that the causal relationship from craniosynostosis to autism is unnecessary for the development of autism spectrum disorder.CONCLUSIONSRegarding the 3 possibilities of the association between craniosynostosis and neurodevelopmental comorbidities proposed by Kapp-Simon’s group, only the independent pathway theory can explain the genotype-phenotype findings. There is no causal relationship between craniosynostosis and autism spectrum disorder in the independent pathway theory. Because the mechanical hindrance of brain expansion from poor compliance of the affected cranial vault is less likely in mild craniosynostosis cases, surgical indication of cranioplasty for mild trigonocephaly should never be confused with that of overt craniosynostosis. If there is no cosmetic indication for the metopic ridge in mild trigonocephaly cases with developmental comorbidities, there is no reason for surgical intervention.

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SMAD6

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