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Effects of Loading and Nutrition on Fascia
Published in David Lesondak, Angeli Maun Akey, Fascia, Function, and Medical Applications, 2020
The connective tissues are largely made from a population of fibroblast cells that contain the high mobility group (HMG) box transcription factor SOX9.7 Even though the cells have a similar origin, once the cells migrate into position and begin being loaded, they differentiate to fit their mechanical environment. In fact, fibroblast cells isolated from connective tissues at different locations in the body become transcriptionally distinct cell types.8 These data suggest that the mechanical environment is essential to driving cell fate. Therefore, understanding the mechanical environment, and the cellular response to load, is essential for maximizing musculoskeletal cell and tissue function.
Breast Cancer Stem Cells and Their Niche: Lethal Seeds in Lethal Soil
Published in Brian Leyland-Jones, Pharmacogenetics of Breast Cancer, 2020
Danuta Balicki, Brian Leyland-Jones, Max S. Wicha
The Wnt family of secreted proteins includes the well-characterized canonical Wnt signaling pathway, in which Wnt ligands signal through the stabilization of β-catenin. In this pathway, Wnt proteins bind to a family of frizzled receptors in a complex with the low-density lipoprotein receptor–related proteins 5 and 6 (LRP5/6) coreceptors to activate Dishevelled (Dsh). Subsequently, Dsh inhibits the activity of the β-catenin destruction complex [adenomatous polyposis coli (APC), axin, and glycogen synthase kinase-3β (GSK-3β)], which phosphorylates β-catenin in the absence of the ligands. As a result, β-catenin is stabilized and translocated to the nucleus, where it recruits transactivators to high mobility group (HMG)-box DNA-binding proteins of the lymphoid-enhancer factor/T-cell factor (LEF/TCF) family. In the absence of Wnt signaling, β-catenin remains in the cytoplasm, where it forms the β-catenin destruction complex. GSK-3β phosphorylates β-catenin, which targets the protein for ubiquitin-mediated degradation. When the Wnt pathway is activated, GSK-3β is inhibited, blocking β-catenin phosphorylation and its subsequent degradation (71). In addition, several β-catenin-independent Wnt signaling pathways, known as noncanonical, have been shown to be crucial for different aspects of vertebrate embryo development (71).
Sex Chromosome Anomalies
Published in Merlin G. Butler, F. John Meaney, Genetics of Developmental Disabilities, 2019
L. Hamerton John, A. Evans Jane
SRY is a transcription factor whose function is to initiate testicular differentiation in mammalian embryogenesis. The protein contains a high mobility group box (HMG), a DNA binding motif conserved among a broad class of nuclear proteins. Almost all of the published mutations associated with sex reversal in 46,XY females are located in the HMG box and affect the structure of the DNA binding domain (146). Other loci involved in XY sex reversal include SOX9 at 17q24, a transcription factor whose duplication leads to XX sex reversal, while mutations lead to XY gonadal dysgenesis and campomelic dysplasia. Mutations in SF1 at 9q33 result in adrenal insufficiency and XY gonadal dysgenesis. Mutations in DMRT1 at 9p24 result in XY gonadal dysgenesis. Mutations at the DAX1 locus, an antitestis gene at Xp21.3, result in congenital adrenal hypoplasia, while duplications of a 160 kb region result in XY gonadal dysgenesis (158). Clearly, extensive genetic heterogeneity exists in both XX and XY sex reversal. The process of sex determination is clearly highly complex and only partially understood (153,158-160).
Molecular study and genotype–phenotype in Chinese female patients with 46, XY disorders of sex development
Published in Gynecological Endocrinology, 2021
Junke Xia, Jing Wu, Chen Chen, Zhenhua Zhao, Yanchuan Xie, Zhouxian Bai, Xiangdong Kong
The SRY gene, encoding 204 amino acids, comprises an evolutionarily conserved DNA-binding domain (DBD), HMG-box, and is flanked by poorly conserved N- and C-terminal segments [19]. SRY mutations account for approximately 15% of 46, XY DSDs, and the majority of mutations are clustered within the HMG domain [19]. HMG domain acts as DNA binding [20]. The novel nonsense mutation (Tyr17Ter) generates a truncated protein before the HMG box. The protein of the variant cannot bind to DNA, causing a loss of protein function. DNA binding is reportedly abolished by Leu94Pro mutation [21]. In P.2, valine occupied this position (Leu94Val), which led to the reduction of DNA-binding affinity. We first reported two novel mutations in female patients with 46, XY DSDs. The patients presented male karyotypes without testicles, showing that SRY mutations prevented bipotential gonads from differentiating into testicles. Sanger sequencing for SRY should be prioritized in patients with 46, XY DSDs without testicles.
SOX13 dependent PAX8 expression promotes the proliferation of gastric carcinoma cells
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Liang-Yu Bie, Dan Li, Yan Wei, Ning Li, Xiao-Bing Chen, Su-Xia Luo
The SOX transcription members are normally expressed in embryonic tissues and stem cells in vivo, to maintain stemness and control differentiation direction [29, 30]. In recent years, it has been found that HMG-box-related transcription factors such as SOX10 and SOX12 are essential for tumour cell survival and growth [31]. For example, SOX10 can synergize with GPM6B and COL9A3 to stimulate EGFR-stimulated proliferation of breast tumour cells, making it a biomarker for diagnosing basal-like breast cancer and a prognostic serum marker [31]. SOX12 is significantly up-regulated in colon cancer and also a biomarker for poor prognosis [32]. Further, SOX12 knockdown can significantly inhibit colon cancer cells proliferation [33]. However, studies on the role of SOX13 in tumours have not been reported. In this study, SOX13 and PAX8 expression in gastric cancer was found to be positive correlated, and highly regulated in tumours than adjacent tissues. Interestingly, SOX13 regulates the expression of PAX8 in gastric cancer cells, and overexpression of SOX13 promotes the expression of PAX8-regulated cell cycle-related genes Aurora B and Cyclin B1. Consistent with this, overexpression of SOX13 can restore cell cycle arrest caused by PAX8 knockdown by restoring the expression of Aurora B and Cyclin B1. These results indicate that SOX13 is involved in the regulation of gastric cancer cell cycle with the role of oncogene in gastric cancer. Overall, our findings reveal an unrecognized function of SOX13 in tumours and look forward to discovering more signalling pathways SOX13 involved.
Functional domain analysis of SOX18 transcription factor using a single-chain variable fragment-based approach
Published in mAbs, 2018
Frank R. Fontaine, Stephen Goodall, Jeremy W. Prokop, Christopher B. Howard, Mehdi Moustaqil, Sumukh Kumble, Daniel T. Rasicci, Geoffrey W. Osborne, Yann Gambin, Emma Sierecki, Martina L. Jones, Johannes Zuegg, Stephen Mahler, Mathias Francois
Across all SOX proteins, the HMG-box shares at least 46% of sequence homology.33 Just outside of this domain, however, SOX homology diverges due to decreased selection pressure.33 In this context, the antibody did indeed recognize both human and mouse SOX18 (Fig. 1B-D), which share 93% homology in this region (Calculated ClustalW similarity score, Fig. 1A), while it did not recognize divergent human SOX2. Interestingly, codon sequence conservation analysis showed that the 8-aa epitope coincides with a highly conserved region (Fig. 2D, black arrow), suggesting an important role in the binding of some SOX18 protein partner.27