Human chromosome 14q32.2 carries a cluster of imprinted genes including paternally expressed genes (PEGs) such as DLK1 and RTL1 and maternally expressed genes (MEGs) such as MEG3 (also known as GTL2), RTL1as (RTL1 antisense) and MEG8 (refs. 1,2), together with the intergenic differentially methylated region (IG-DMR) and the MEG3-DMR. Consistent with this, paternal and maternal uniparental disomy for chromosome 14 (upd(14)pat and upd(14)mat) cause distinct phenotypes. We studied eight individuals (cases 1-8) with a upd(14)pat-like phenotype and three individuals (cases 9-11) with a upd(14)mat-like phenotype in the absence of upd(14) and identified various deletions and epimutations affecting the imprinted region. The results, together with recent mouse data, imply that the IG-DMR has an important cis-acting regulatory function on the maternally inherited chromosome and that excessive RTL1 expression and decreased DLK1 and RTL1 expression are relevant to upd(14)pat-like and upd(14)mat-like phenotypes, respectively.
Although chromosome X open reading frame 6 (CXorf6) has been shown to be a causative gene for hypospadias, its molecular function remains unknown. To clarify this, we first examined CXorf6 protein structure, identifying homology to mastermindlike 2 (MAML2) protein, which functions as a co-activator in canonical Notch signaling. Transactivation analysis for wildtype CXorf6 protein by luciferase assays showed that CXorf6 significantly transactivated the promoter of a noncanonical Notch target gene hairy/enhancer of split 3 (Hes3) without demonstrable DNA-binding capacity. Transactivation analysis was also performed for the previously described three apparently pathologic nonsense mutations, indicating that E124X and Q197X proteins had no transactivation function, whereas R653X protein retained a nearly normal transactivation function. Subcellular localization analysis revealed that wild-type and R653X proteins co-localized with MAML2 protein in nuclear bodies, whereas E124X and Q197X proteins were incapable of localizing to nuclear bodies. Thus, further studies were performed for R653X, revealing the occurrence of nonsense mediated mRNA decay in vivo. Next, transient knockdown of CXorf6 was performed using small interfering RNA, showing reduced testosterone production in mouse Leydig tumor cells. Furthermore, steroidogenic factor 1 (SF1) protein bound to a specific sequence in the upstream of the CXorf6 coding region and exerted a transactivation activity. These results suggest that CXorf6 transactivates the Hes3 promoter, augments testosterone production, and contains the SF1 target sequence, thereby providing the first clue to clarify the biological role of CXorf6. We designate CXorf6 as MAMLD1 (mastermind-like domaincontaining 1) based on its characteristic structure.
Involvement of hepatocyte growth factor (HGF) in lung morphogenesis and regeneration has been established by in vitro and in vivo experiments in animals. In the present study, the protective activity of HGF against tumor necrosis factor (TNF)-␣ or hydrogen peroxide (H 2 O 2 )-induced damage of pulmonary epithelial cells was examined using the human small airway epithelial cell line (SAEC). Western blot analysis revealed that the receptor for HGF (c-Met) was highly expressed on the surface of SAEC and its downstream signal transduction pathway was functional. The SAEC was induced into apoptosis by the treatment with TNF-␣ or H 2 O 2 in a dose-dependant manner, but was significantly rescued from apoptosis in the presence of HGF. The HGF effect was evident when added not only at the same time but also within several hours after treatment. This protective activity of HGF against the TNF-␣-or H 2 O 2 -induced apoptosis was mediated, at least in part, by up-regulating the nuclear factor B activity and an increase in the ratio of apoptosis-suppressing to apoptosis-inducing proteins. These results suggest that administration of HGF might exhibit a potent function in vivo for protection and improvement of acute and chronic lung injuries induced by inflammation and/or oxidative stress. Lung development and morphogenesis begin in the fetal period of embryo and finally reach the formation of mature alveolar cells around 36 wk of gestation. The control of lung development is complicated and known to be influenced by the interaction between pulmonary epithelial and mesenchymal cells, which is mainly mediated by autocrine and paracrine mechanisms via a variety of polypeptides expressed on or secreted from mesenchymal cells (1).HGF, which was originally purified and cloned as a potent mitogen for mature hepatocytes in primary culture (2-4), is a cytokine mainly produced by cells of mesenchymal origin (5). Previous studies have demonstrated that HGF has multifunctional activities such as mitogenic, morphogenic, and motogenic on a variety of epithelial cells (5, 6), including pulmonary epithelial cells (7). Pulmonary mesenchymal cells synthesize and secrete HGF, which has been shown to be involved not only in the formation of bronchoalveolar structure during fetal development, but also in the repair process of injured distal organs such as liver and kidney (7-10). In the bleomycin-induced lung injury model in rats (11), HGF showed the proliferative effect on type II alveolar epithelial cells, but showed the antiproliferative effect on alveolar macrophages and fibroblasts mainly implicated in the occurrence of fibrotic changes of the lung. In addition, it has recently been shown that endogenous and exogenous HGF protects cardiac myocytes in a rat model of ischemia/reperfusion injury (12) and that the addition of HGF in the culture effectively protects adult rat cardiac myocytes from oxidative stress-induced apoptosis (13). Thus, it is speculated that HGF might play a role in the physiologic repair process of respiratory epithelium...
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