Gnathodiaphyseal dysplasia (GDD) is a rare skeletal syndrome characterized by bone fragility, sclerosis of tubular bones, and cemento-osseous lesions of the jawbone. By linkage analysis of a large Japanese family with GDD, we previously mapped the GDD locus to chromosome 11p14.3-15.1. In the critical region determined by recombination mapping, we identified a novel gene (GDD1) that encodes a 913-amino-acid protein containing eight putative transmembrane-spanning domains. Two missense mutations (C356R and C356G) of GDD1 were identified in the two families with GDD (the original Japanese family and a new African American family), and both missense mutations occur at the cysteine residue at amino acid 356, which is evolutionarily conserved among human, mouse, zebrafish, fruit fly, and mosquito. Cellular localization to the endoplasmic reticulum suggests a role for GDD1 in the regulation of intracellular calcium homeostasis.
. Osteoactivin upregulates expression of MMP-3 and MMP-9 in fibroblasts infiltrated into denervated skeletal muscle in mice. Am J Physiol Cell Physiol 289: C697-C707, 2005; doi:10.1152/ajpcell.00565.2004.-In this study, we examined pathophysiological roles of osteoactivin, a functionally unknown type I membrane glycoprotein, in mouse skeletal muscle atrophied by denervation (sciatic neurectomy). Denervation increased the amounts of osteoactivin, vimentin, matrix metalloproteinase-3 (MMP-3), and MMP-9 in mouse gastrocnemius muscle. Interestingly, immunohistochemical analysis revealed that vimentin, MMP-3, and MMP-9 were mainly present in fibroblast-like cells infiltrated into denervated mouse gastrocnemius muscle, whereas osteoactivin was expressed in the sarcolemma of myofibers adjacent to the fibroblast-like cells. On the basis of these findings, we reasoned that osteoactivin in myocytes was involved in activation of the infiltrated fibroblasts. To address this issue, we examined effects of osteoactivin on expression of MMPs in fibroblasts in vitro and in vivo. Overexpression of osteoactivin in NIH-3T3 fibroblasts induced expression of MMP-3, but not in mouse C 2C12 myoblasts, indicating that osteoactivin might functionally target fibroblasts. Treatment with recombinant mouse osteoactivin increased the amounts of collagen type I, MMP-3, and MMP-9 in mouse NIH-3T3 fibroblasts. The upregulated expression of these fibroblast marker proteins was significantly inhibited by heparin, but not by an integrin inhibitor, indicating that a heparin-binding motif in the extracellular domain might be an active site of osteoactivin. In osteoactivin-transgenic mice, denervation further enhanced expression of MMP-3 and MMP-9 in fibroblasts infiltrated into gastrocnemius muscle, compared with wild-type mice. Our present results suggest that osteoactivin might function as an activator for fibroblasts infiltrated into denervated skeletal muscles and play an important role in regulating degeneration/regeneration of extracellular matrix. sciatic neurectomy; Gpnmb family; C2C12 cells; NIH-3T3 cells; osteoactivin-transgenic mice DENERVATION (sciatic neurectomy) causes numerous changes in contractile, electrical, metabolic, and molecular properties of the muscle fiber membrane and sarcoplasm in hindlimb skeletal muscles (6, 10). Previous studies (21,22,32) have shown evidence that denervation alters interstitial spaces between muscle fibers: mononucleated cells are infiltrated into interstitial spaces of muscle fibers, and fibrosis occasionally occurs in the muscle. These findings suggest that the interaction between muscle fiber membrane and infiltrated cells might play an important role in degeneration or regeneration of denervated skeletal muscle. However, information on the interaction between the muscle fiber membrane and infiltrated cells is very little.To address this issue, we previously examined the expression of ϳ26,000 genes in rat gastrocnemius muscle atrophied by denervation or spaceflight using an Affymetrix DNA microarray...
Activin, a member of the TGF- superfamily, regulates the growth and differentiation of a variety of cell types. Based on the expression of activin in pancreatic rudiments of rat embryos and stimulation of insulin secretion from adult rat pancreatic islets by activin, activin is implicated in the development and function of islets. To examine the significance of activin signaling in the fetal and postnatal development of islets, transgenic mice expressing a dominant negative form of activin receptor (dn-ActR) or a constitutively active form of activin receptor (ActR-T206D) in islets were generated together with the transgenic mice expressing intact activin receptor (intact ActR) as a negative control. Transgenic mice with both dn-ActR and ActR-T206D showed lower survival rates, smaller islet area, and lower insulin content in the whole pancreas with impaired glucose tolerance when compared with transgenic mice with intact ActR or littermates, but they showed the same ␣ cell/  cell ratios as their littermates. In addition to islet hypoplasia, the insulin response to glucose was severely impaired in dnActR transgenic mice. It is suggested that a precisely regulated intensity of activin signaling is necessary for the normal development of islets at the stage before differentiation into ␣ and  cells, and that activin plays a role in the postnatal functional maturation of islet  cells. ( J. Clin. Invest. 1998. 102:294-301.)
Amrubicin is a novel, completely synthetic 9-aminoanthracycline derivative. Amrubicin and its C-13 alcohol metabolite, amrubicinol, inhibited purified human DNA topoisomerase II (topo II). Compared with doxorubicin (DXR), amrubicin and amrubicinol induced extensive DNA-protein complex formation and double-strand DNA breaks in CCRF-CEM cells and KU-2 cells. In this study, we found that ICRF-193, a topo II catalytic inhibitor, antagonized both DNA-protein complex formation and double-strand DNA breaks induced by amrubicin and amrubicinol. Coordinately, cell growth inhibition induced by amrubicin and amrubicinol, but not that induced by DXR, was antagonized by ICRF-193. Taken together, these findings indicate that the cell growthinhibitory effects of amrubicin and amrubicinol are due to DNA-protein complex formation followed by double-strand DNA breaks, which are mediated by topo II.Key words: Amrubicin -Anthracycline -DNA-protein complex -Double-strand DNA break -DNA topoisomerase II DNA topoisomerase II (topo II) is a nuclear enzyme that regulates DNA topology through strand breakage, strand passage and religation. Thus, topo II is extensively involved in DNA metabolism, including replication, transcription, recombination and sister chromatid segregation.1) Mammalian topo II is the primary cellular target of a number of potent antitumor agents such as doxorubicin (DXR), daunorubicin (DNR), etoposide and amsacrine (m-AMSA).2) These agents interfere with the breakagereunion reaction of topo II by trapping a covalent enzyme-DNA complex, termed "cleavable complex," in which DNA strands are broken and their 5′ termini are covalently linked to the protein. In general, the cytotoxicity of these topo II poisons is dependent on stabilization of the cleavable complex followed by topo II-mediated DNA damage, rather than inactivation of topo II cellular functions. 3)Amrubicin is a novel, completely synthetic 9-aminoanthracycline derivative, and has antitumor activities in murine experimental tumor systems and human tumornude mouse systems. 4,5) Like other anthracycline derivatives, such as DXR and DNR, amrubicin is converted to its C-13 alcohol metabolite, amrubicinol.6) In contrast to doxorubicinol and daunorubicinol, amrubicinol has much higher antitumor activity than the parent drug in vitro. 6, 7)In addition, amrubicin showed much weaker cardiotoxicity than DXR in a rabbit chronic experimental model. 8)Phase II clinical trials of amrubicin for the treatment of malignant lymphoma, superficial bladder, small cell lung carcinoma, and non-small cell lung carcinoma are in progress. 9,10) Amrubicin showed substantial activity (response rate of 25%) against non-small cell lung cancer, and a response rate of 78.8% was obtained against small cell lung cancer.The mechanisms underlying the antitumor activities of amrubicin and amrubicinol are not well understood. Our present study has shown that amrubicin and amrubicinol target human topo II by stabilizing the cleavable complex. Furthermore, amrubicin and amrubicinol induced DNApro...
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.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.