Retinoic acid, thyroid hormone, and vitamin D receptors preferentially activate target genes through response elements that consist of direct repeat arrangements of a core recognition motif of consensus sequence AGGTCA. We present evidence that the preference for direct repeat elements arises from two fundamental differences from steroid hormone receptors. First, retinoic acid, thyroid hormone, and vitamin D receptors are demonstrated to preferentially form heterodimers with the retinoid X receptors. These interactions are mediated by the carboxy-terminal dimerization interface, with heterodimer preference specified by actions of the DNA-binding domain. Second, the DNA-binding domains of heterodimeric receptors appear to be rotationally flexible with respect to the carboxy-terminal dimerization interface. Several independent lines of evidence suggest that, relative to the retinoid X and steroid hormone receptors, the DNA-binding domain of the thyroid hormone receptor is preferentially rotated by -180 ~ with respect to its carboxy-terminal dimerization interface. As a result, solution interactions between the carboxy-terminal dimerization interfaces of the retinoid X and thyroid hormone receptors are predicted to lead to the preferential alignment of their respective DNA-binding domains in a direct repeat configuration. This alignment would position the retinoid X receptor over the upstream recognition motif of direct repeat response elements. Differential orientations of the DNA-binding domain, which contribute to the polarity of heterodimer binding, are regulated by a short sequence (the A box) that is located between the conserved DNA-binding and carboxy-terminal dimerization domains.[Key Words: Nuclear receptor heterodimersl DNA-binding domain~ carboxy-terminal dimerization interface] Received April 9, 1993~ revised version accepted May 13, 1993.The thyroid hormone, retinoic acid, and vitamin D receptors [TR, RAR, and VDR, respectively} are members of the nuclear receptor superfamily of ligand-dependent transcription factors that interact with response elements in target genes and thereby control diverse aspects of development and homeostasis (Evans 1988~ Beato 1989~ Glass and Rosenfeld 1991}. A central problem in understanding the actions of these and related nuclear receptors is the elucidation of the molecular mechanisms by which target genes are recognized. Studies of the DNA-binding properties of the TR, RAR, and VDR SCorgesponding author. 6Present address:
Immunosuppressive/anti-inflammatory macrophage (Mφ), M2-Mφ that expressed the typical M2-Mφs marker, CD206, and anti-inflammatory cytokine, interleukin (IL)-10, is beneficial and expected tool for the cytotherapy against inflammatory diseases. Here, we demonstrated that bone marrow-derived lineage-positive (Lin+) blood cells proliferated and differentiated into M2-Mφs by cooperation with the bone marrow-derived mesenchymal stem cells (MSCs) under hypoxic condition: MSCs not only promoted proliferation of undifferentiated M2-Mφs, pre-M2-Mφs, in the Lin+ fraction via a proliferative effect of the MSCs-secreted macrophage colony-stimulating factor, but also promoted M2-Mφ polarization of the pre-M2-Mφs through cell-to-cell contact with the pre-M2-Mφs. Intriguingly, an inhibitor for intercellular adhesion molecule (ICAM)-1 receptor/lymphocyte function-associated antigen (LFA)-1, Rwj50271, partially suppressed expression of CD206 in the Lin+ blood cells but an inhibitor for VCAM-1 receptor/VLA-4, BIO5192, did not, suggesting that the cell-to-cell adhesion through LFA-1 on pre-M2-Mφs and ICAM-1 on MSCs was supposed to promoted the M2-Mφ polarization. Thus, the co-culture system consisting of bone marrow-derived Lin+ blood cells and MSCs under hypoxic condition was a beneficial supplier of a number of M2-Mφs, which could be clinically applicable to inflammatory diseases.
We investigated whether transforming growth factor (TGF)-β1 promoted epithelial-mesenchymal transition (EMT) and migration of human oral squamous cell carcinoma (hOSCC) cells. Among 6 hOSCC cell lines investigated, Smad2 phosphorylation and TGF-β target genes expression were most clearly upregulated following TGF-β1 stimulation in HSC-4 cells, indicating that HSC-4 cells were the most responsive to TGF-β1. In addition, the expression levels of the mesenchymal markers N-cadherin and vimentin were most clearly induced in HSC-4 cells among the hOSCC cell lines by TGF-β1 stimulation. Interestingly, E-cadherin and β-catenin at the cell surface were internalized in HSC-4 cells stimulated with TGF-β1. In addition, the expression levels of the EMT-related transcription factor Slug was significantly upregulated on TGF-β1 stimulation. Moreover, the downregulation of Slug by RNA interference clearly inhibited the TGF-β1-induced expression of mesenchymal marker and the migration of HSC-4 cells. Proteomics analysis also revealed that the expression levels of integrin α3β1-targeted proteins were upregulated in TGF-β1-stimulated HSC-4 cells. Neutral antibodies against integrin α3 and β1, as well as a focal adhesion kinase (FAK) inhibitor, clearly suppressed TGF-β1-induced cell migration. These results suggest that the EMT and integrin α3β1/FAK pathway-mediated migration of TGF-β1-stimulated HSC-4 hOSCC cells is positively controlled by Slug.
Background/Aims: Remodeling of fibrous and vascular tissues in the periodontal ligament (PDL) around the tooth root was observed during tooth movement by orthodontic force application. We previously demonstrated that a single cell-derived culture (SCDC) of primarily cultured PDL fibroblasts, called SCDC2, has an endothelial progenitor cell (EPC)-like character and can form endothelial cell (EC) marker-positive blood vessel-like structures. However, the types of molecular mechanisms that control the in vivo kinetic properties and the differentiation of the PDL-derived EPC-like cells into myofibroblasts (MFs), which are known to expand fibrous tissues, require clarification. Methods: Using specific mitogen activated protein kinase (MAPK) inhibitors, we examined how epidermal growth factor (EGF)-mediated MAPK signals affected the proliferation, migration, and MF differentiation of these cells. Results: EGF induced SCDC2 cell proliferation in MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK)- and c-Jun N-terminal kinase (JNK)-dependent manners. In addition, EGF suppressed the expression of MF differentiation markers in these cells in a MEK/ERK-dependent manner, and, moreover, stimulated the cell migration in a MEK/ERK-dependent manner. Conclusion: EGF regulates fibrous tissue remodeling in PDLs through MEK/ERK- and JNK-mediated signals by affecting the proliferation, migration, and MF differentiation of the PDL-derived EPC-like cells.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.