• Aging
• Carcinogenesis
• Stomach
• Transforming growth factor-β
• Wnt
• β-catenin

• Androgen receptor
• Apoptosis
• E2F
• Prostate cancer
• p14ARF

In this study, we aimed to investigate the molecular basis of lactation as well as to identify the genetic factors that influence milk yield and composition in goats. To achieve these two goals, we have analyzed how the mRNA profile of the mammary gland changes in seven Murciano-Granadina goats at each of three different time points, i.e. 78 d (T1, early lactation), 216 d (T2, late lactation) and 285 d (T3, dry period) after parturition. Moreover, we have performed a genome-wide association study (GWAS) for seven dairy traits recorded in the 1st lactation of 822 Murciano-Granadina goats.

The expression profiles of the mammary gland in the early (T1) and late (T2) lactation were quite similar (42 differentially expressed genes), while strong transcriptomic differences (more than one thousand differentially expressed genes) were observed between the lactating (T1/T2) and non-lactating (T3) mammary glands. A large number of differentially expressed genes were involved in pathways related with the biosynthesis of amino acids, cholesterol, triglycerides and steroids as well as with glycerophospholipid metabolism, adipocytokine signaling, lipid binding, regulation of ion transmembrane transport, calcium ion binding, metalloendopeptidase activity and complement and coagulation cascades. With regard to the second goal of the study, the performance of the GWAS allowed us to detect 24 quantitative trait loci (QTLs), including three genome-wide significant associations: QTL1 (chromosome 2, 130.72-131.01 Mb) for lactose percentage, QTL6 (chromosome 6, 78.90-93.48 Mb) for protein percentage and QTL17 (chromosome 17, 11.20 Mb) for both protein and dry matter percentages. Interestingly, QTL6 shows positional coincidence with the casein genes, which encode 80% of milk proteins.

The abrogation of lactation involves dramatic changes in the expression of genes participating in a broad array of physiological processes such as protein, lipid and carbohydrate metabolism, calcium homeostasis, cell death and tissue remodeling, as well as immunity. We also conclude that genetic variation at the casein genes has a major impact on the milk protein content of Murciano-Granadina goats.

• Casein genes
• Dairy traits
• GWAS
• Lactation
• QTLs
• RNA-Seq

• Cancer
• Co-factors
• Heart development
• Limb development
• Lung development
• Mammary gland development
• Obesity
• Rheumatoid arthritis
• Signalling
• Stem cells
• T-box factors
• TBX3
• Target genes
• Transcription factor
• Ulnar mammary syndrome

• Animals
• Cell Transformation, Neoplastic/genetics
• Cell Transformation, Neoplastic/pathology
• Disease/genetics
• Gene Expression Regulation, Developmental/genetics
• Humans
• T-Box Domain Proteins/genetics
• Transcription Factors/genetics

• R01 GM089820 NIGMS NIH HHS

• S-phase
• TBX3
• c-Myc
• cell cycle
• cyclin A-CDK2
• phosphorylation
• transcription

• Breast cancer
• Ductal carcinoma in situ
• Epithelial-mesenchymal transition
• Invasive mammary carcinoma
• TBX3

• Cancer
• TBX3
• Transcription factor
• p21WAF1

Sarcomas represent a complex group of malignant neoplasms of mesenchymal origin and their heterogeneity poses a serious diagnostic and therapeutic challenge. There is therefore a need to elucidate the molecular mechanisms underpinning the pathogenesis of the more than 70 distinguishable sarcoma subtypes. The transcription factor TBX3, a critical developmental regulator, is overexpressed in several cancers of epithelial origin where it contributes to tumorigenesis by different molecular mechanisms. However, the status and role of TBX3 in sarcomas have not been reported. Here we show that a diverse subset of soft tissue and bone sarcoma cell lines and patient-derived sarcoma tissues express high levels of TBX3. We further explore the significance of this overexpression using a small interferring RNA approach and demonstrate that TBX3 promotes the migratory ability of chondrosarcoma, rhabdomyosarcoma and liposarcoma cells but inhibits fibrosarcoma cell migration. This suggested that TBX3 may play a key role in the development of different sarcoma subtypes by functioning as either an oncoprotein or as a brake to prevent tumour progression. To further explore this, TBX3 knockdown and overexpression cell culture models were established using chondrosarcoma and fibrosarcoma cells as representatives of each scenario, and the resulting cells were characterized with regard to key features of tumorigenesis. Results from in vitro and in vivo assays reveal that, while TBX3 promotes substrate-dependent and -independent cell proliferation, migration and tumour formation in chondrosarcoma cells, it discourages fibrosarcoma formation. Our findings provide novel evidence linking TBX3 to cancers of mesenchymal origin. Furthermore, we show that TBX3 may be a biomarker for the diagnosis of histologically dynamic sarcoma subtypes and that it impacts directly on their oncogenic phenotype. Indeed, we reveal that TBX3 may exhibit oncogene or tumour suppressor activity in sarcomas, which suggests that its role in cancer progression may rely on cellular context.

• TBX3
• breast cancer
• driver mutation
• frameshift mutation
• in-frame deletion
• p21
• somatic mutations

The transcription factors TBX2 and TBX3 are overexpressed in various human cancers. Here, we investigated the effect of overexpressing the orthologous Tbx genes Drosophila optomotor-blind (omb) and human TBX2 in the epithelium of the Drosophila wing imaginal disc and observed two types of cell motility. Omb/TBX2 overexpressing cells could move within the plane of the epithelium. Invasive cells migrated long-distance as single cells retaining or regaining normal cell shape and apico-basal polarity in spite of attenuated apical DE-cadherin concentration. Inappropriate levels of DE-cadherin were sufficient to drive cell migration in the wing disc epithelium. Omb/TBX2 overexpression and reduced DE-cadherin-dependent adhesion caused the formation of actin-rich lateral cell protrusions. Omb/TBX2 overexpressing cells could also delaminate basally, penetratingthe basal lamina, however, without degradation of extracellular matrix. Expression of Timp, an inhibitor of matrix metalloproteases, blocked neither intraepithelial motility nor basal extrusion. Our results reveal an MMP-independent mechanism of cell invasion and suggest a conserved role of Tbx2-related proteins in cell invasion and metastasis-related processes.

• Cancer
• Cancer therapy
• T-box factors
• TBX2
• Transcription factors

• Animals
• DNA Damage
• Humans
• Neoplasms/pathology
• Signal Transduction
• T-Box Domain Proteins/physiology

• MAC-T
• T-box2
• T-box3
• mammary gland

TBX3 is a member of the T-box family of transcription factors with critical roles in development, oncogenesis, cell fate, and tissue homeostasis. TBX3 mutations in humans cause complex congenital malformations and Ulnar-mammary syndrome. Previous investigations into TBX3 function focused on its activity as a transcriptional repressor. We used an unbiased proteomic approach to identify TBX3 interacting proteins in vivo and discovered that TBX3 interacts with multiple mRNA splicing factors and RNA metabolic proteins. We discovered that TBX3 regulates alternative splicing in vivo and can promote or inhibit splicing depending on context and transcript. TBX3 associates with alternatively spliced mRNAs and binds RNA directly. TBX3 binds RNAs containing TBX binding motifs, and these motifs are required for regulation of splicing. Our study reveals that TBX3 mutations seen in humans with UMS disrupt its splicing regulatory function. The pleiotropic effects of TBX3 mutations in humans and mice likely result from disrupting at least two molecular functions of this protein: transcriptional regulation and pre-mRNA splicing.

TBX3 is a protein with essential roles in development and tissue homeostasis, and is implicated in cancer pathogenesis. TBX3 mutations in humans cause a complex of birth defects called Ulnar-mammary syndrome (UMS). Despite the importance of TBX3 and decades of investigation, few TBX3 partner proteins have been identified and little is known about how it functions in cells. Unlike previous investigations focused on TBX3 as DNA binding factor that represses transcription, we took an unbiased approach to identify TBX3 partner proteins in mouse embryos and human cells. We discovered that TBX3 interacts with RNA binding proteins and binds mRNAs to regulate how they are spliced. The different mutations seen in human UMS patients produce mutant proteins that interact with different partners and have different splicing activities. TBX3 promotes or inhibits splicing depending on cellular context, its partner proteins, and the target mRNA. Eukaryotic cells have many more proteins than genes: alternative splicing is critical to generate the different mRNAs needed for production of the specific and vast repertoire of proteins a cell produces. Our finding that TBX3 regulates this process provides fundamental new insights into how altered quantity and molecular function of TBX3 contribute to human developmental disorders and cancer.

• tbx2
• tbx3
• mammary development
• breast cancer
• transcription factor
• t-box

• Animals
• Breast Neoplasms/genetics
• Breast Neoplasms/pathology
• Female
• Gene Expression Regulation, Developmental
• Humans
• Mammary Glands, Animal/growth & development
• Mammary Glands, Human/growth & development
• T-Box Domain Proteins/genetics
• T-Box Domain Proteins/physiology

• K12 HD000849 NICHD NIH HHS
• R37 HD033082 NICHD NIH HHS
• K12HD000849 NICHD NIH HHS
• R37HD033082 NICHD NIH HHS

• TBX2
• TBX3
• invasion
• melanoma
• senescence

• bone
• differentiation
• osteoblast
• transcription factor
• t-box3

• Animals
• Biomarkers
• Cell Differentiation
• Cells, Cultured
• Core Binding Factor Alpha 1 Subunit/genetics
• Core Binding Factor Alpha 1 Subunit/metabolism
• Gene Expression Regulation/genetics
• Humans
• Mice
• Osteoblasts/cytology
• Osteoblasts/metabolism
• Sp7 Transcription Factor
• T-Box Domain Proteins/genetics
• T-Box Domain Proteins/metabolism
• Transcription Factors/genetics
• Transcription Factors/metabolism

• R01 AR048139 NIAMS NIH HHS
• R56 AR048139 NIAMS NIH HHS
• AR048139 NIAMS NIH HHS