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Developmental Diseases of the Nervous System
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
James H. Tonsgard, Nikolas Mata-Machado
HHT has an autosomal dominant inheritance. Linkage analysis indicates at least five genes, four of which have been identified. The genes for HHT are located in the transforming growth factor beta (TGF-β) signaling pathway that regulates cell proliferation, differentiation, apoptosis, and migration. Mutations in endoglin or ENG, activin receptor-like kinase or ALK1/ACVRL, and Smad 4, cause JJT1, HHT2, and the combined juvenile polyposis HHT syndrome, respectively. Endoglin and ACVRL1 mutations are seen in roughly 85% of cases. Smad4 mutations are seen in less than 2% of cases. Mutations in bone morphogenetic 9 protein (BMP9 – GDF2 gene) have been reported in some patients. This gene exerts its effects by binding to specific endothelial cell surface receptors, which leads to the association of Smad proteins that regulate gene expression in endothelial cells. Approximately 15% of patients who appear to have HHT clinically do not have identifiable mutations. Additional genes are predicted on chromosome 5 (HHT3) and chromosome 7 (HHT4).
Bone morphogenetic protein (BMP)9 in cancer development: mechanistic, diagnostic, and therapeutic approaches?
Published in Journal of Drug Targeting, 2023
Ali G. Alkhathami, Mustafa Ryadh Abdullah, Muhjaha Ahmed, Hanan Hassan Ahmed, Sarab W. Alwash, Zahra Muhammed Mahdi, Fahad Alsaikhan, Ayed A. Dera
Bone morphogenetic protein 9 (BMP9, also called GDF2 (growth differentiation factor 2)), one of the recently discovered members of the BMPs, was first found to be expressed in the developing mouse liver. Other than induction of bone formation orthotopically and ectopically, this BMP has also been involved in several biological functions, including cholinergic neurons differentiation, haematopoietic progenitor cells proliferation, regulation of reticular endothelial system in the liver, angiogenesis, and glucose metabolism [10].
Identification of key pathways and genes in the progression of silicosis based on WGCNA
Published in Inhalation Toxicology, 2022
Jiaqi Lv, Jingwei Xiao, Qiang Jia, Xiangjing Meng, Zhifeng Yang, Shuangshuang Pu, Ming Li, Tao Yu, Yi Zhang, Haihua Wang, Li Liu, Zhongsheng Li, Xiao Chen, Haitao Yang, Yulu Li, Mengyun Qiao, Airu Duan, Hua Shao, Bin Li
In light of the importance of the black and purple modules in silicosis fibrosis, we screened the hub genes in the two modules, some of which were key regulators of the Hippo signaling pathway. Previous studies have shown that RNF187 knockout can increase YAP and Hippo signaling target genes, such as CTGF in Triple-negative breast cancer (Wang et al. 2020); overexpression of RNF187 was found to induce cell epithelial-mesenchymal transition (EMT) in non-small-cell lung cancer (Fu et al. 2019); YAP was expressed in fibrotic lung tissues and immortalized fibroblasts expressing active YAP can promote fibrosis when adoptively transferred to the murine lung (Liu et al. 2015). Given the central role of YAP in the Hippo signaling pathway and mechanotransduction and cell-cell contact, it is not a surprise to find that the crosstalk between Gdf2 (also named BMP9) and Hippo signaling pathway (YAP1, Smad, Zyxin) can regulate extracellular matrix (ECM) metabolism in endothelial cells; the secretion of CTGF regulates the composition and function of focal adhesion proteins, cell migration and ECM remodeling, and acts as a key effector of BMP9 signaling (Young et al. 2015). Moreover, the above research is reminiscent of interesting reports, importantly including the demonstration that Dhrs9 can modulate the synthesis of retinoic acid, inhibition of which by the activation of YAP signaling and epithelial-mesenchymal fibroblast growth factor (FGF) signaling, stimulated mouse lung epithelial proliferation (Ng-Blichfeldt et al. 2018). Besides CTGF and FGF, Wt1 is also an important target gene of YAP: YAP may regulate proliferation, EMT, and fate determination of epicardial cells in part by directly modulating Wt1 expression (Singh et al. 2016).YAP, as a transcription co-activator, often exerts its function with other protein molecules such as CHRAC1, which can indirectly bind to YAP in lung cancer cells and enhance the transcription of downstream target oncogenes (CTGF, etc.) in the Hippo pathway, suggesting a critical role of CHRAC1 in promoting YAP transcriptional activity (Wang et al. 2022). Moreover, PPP1CC, one of the catalytic subunits of PP1 (protein phosphatase 1), may inhibit the Hippo pathway by suppressing Large Tumor Suppressor 1/2 (LATS1/2) and subsequently activating YAP/TAZ via inhibiting the phosphorylation and activation of KIBRA (a WW domain-containing protein) (Xiao et al. 2011). Another key gene in Hippo signaling pathway deserving further investigation is PP2Ac (despite its absence in WGCNA). PP2A regulates many key cellular processes such as the cell cycle, cell growth, survival, apoptosis and signal transduction (Sangodkar et al. 2016). In terms of fibrosis injury, it has been reported that PP2Ac has a profound effect on the advancement of fibrosis in many tissues and organs (liver fibrosis induced by CCl4, pulmonary fibrosis caused by bleomycin, renal fibrosis driven by TGF-β1) (Lu et al. 2015; Deng et al. 2016; Sun et al. 2019). Consequently, although no directly relevant evidence has demonstrated the linkage between the genes discussed above and pulmonary fibrosis inducible by silica, further in-depth exploration of the role of the aforementioned genes in silicosis fibrosis is highly likely to make a major breakthrough in this field of expertise.