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1.
Regulation of chondrocyte differentiation by Cbfa1   总被引:18,自引:0,他引:18  
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Patched (Ptch) is a receptor in the hedgehog signaling pathway, essential for animal development. Our previous study showed that ptch1 gene participates in the maintenance of the male germline and spermatogenesis in Cynoglossus semilaevis (csptch1). In this study, we identified a patched1 gene homolog (csptch1 x1). The csptch1 x1 gene is 5761 bp long, with a 4638 bp coding sequence that encodes 1545 amino acids. The Csptch1 x1 protein has 12 transmembrane regions and sterol-sensing domains and is highly homologous to the csptch1 (91 amino acids difference). Expression pattern analysis showed that csptch1 x1 is expressed in eight different tissues of adult tongue sole, and the expression is significantly higher in tissues of female than that in male tissues. The expression pattern in developmental stages was also analyzed. csptch1 x1 could be detected at the 1-cell stage and was highly expressed at the blastocyst, somite, and blastopore closing stages, implying that it participates in cell differentiation. In ovarian development, the expression of csptch1 x1 was initiated at 20 days after hatching (dah) and was significantly high at 35–50 and 95–150 dah. In situ hybridization showed that csptch1 x1 was predominantly expressed in primordial germ cells, oocytes, and follicular cells, but the expression of the gene was lower in the testis. These results suggest that csptch1 x1 may be mainly involved in female differentiation and ovarian development, different from the role of csptch1 in spermatogenesis.  相似文献   

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Cbfa1/Runx2与成骨细胞分化调控   总被引:9,自引:0,他引:9  
成骨细胞是由间充质干细胞经骨原细胞和前成骨细胞分化而来的。近年来已鉴定转录因子Cbfal(core binding factor α1)是成骨细胞分化和骨形成的关键调控因子。在成骨细胞分化的过程中,Cbfal通过调控成骨细胞特异性细胞外基质蛋白基因的表达和成骨细胞周期参与成骨细胞的分化过程。新近发现Cbfal能通过自身的PST序列区域与Smads结合形成复合物共同参与成骨细胞的分化调控。  相似文献   

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低氧诱导因子和白血病细胞分化   总被引:3,自引:0,他引:3  
三氧化二砷(As2O3,ATO)是一种新发现的有效治疗急性早幼粒细胞白血病(acute promyelocytic leukemia,APL)的药物。研究发现,该药物在体外诱导细胞分化的能力不如体内明显。以此为基础,最近我们意外地发现模拟低氧化合物和中度低氧环境能够直接在体外诱导急性髓系白血病细胞分化,也选择性地加强三氧化二砷诱导的APL细胞分化。进一步地,间歇性低氧能够显著延长移植的白血病小鼠生存时间,并且抑制白血病细胞浸润并诱导其分化。以这些工作为基础,我们就低氧诱导白血病细胞分化的分子机制进行了深入研究。本文将就相关工作作一综述,并讨论有待进一步研究的问题。  相似文献   

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SCC4 human keratinocytes are derived from a squamous cell carcinoma of the tongue and undergo very little spontaneous differentiation. Introduction of a wild-type beta 1 integrin subunit into SCC4 cells stimulates differentiation, suggesting either that the cells have a defect in the integrin signaling pathways that control differentiation or that the beta1 subunit itself is defective. Here we describe a heterozygous mutation in the SCC4 beta 1 subunit. The mutation, T188I, maps to the I-like domain. It results in constitutive activation of ligand binding, irrespective of the partner alpha subunit, in solid phase assays with recombinant protein and in living cells. The mutation promotes cell spreading, but not proliferation, motility, or invasiveness. It results in sustained activation of Erk MAPK independent of cell spreading. When introduced into SCC4 keratinocytes, the wild-type beta1 integrin stimulates differentiation, whereas the mutant is inactive. Activation of beta 1 integrins in normal keratinocytes also suppresses differentiation. These results establish, for the first time, mutation as a mechanism by which integrins can contribute to neoplasia, because the degree of differentiation in epithelial cancers is inversely correlated with prognosis. They also provide new insights into how integrins regulate keratinocyte differentiation.  相似文献   

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Despite the success of immunotherapy in several haematological neoplasms, the effectiveness in acute myeloid leukaemia (AML) is still controversial, partially due to the lack of knowledge regarding immune‐related processes in this disease and similar neoplasias. In this study, we analysed the role and expression of histamine receptor 1 (HRH1) in haematological malignancies. Although the histamine receptor type 1 was widely expressed in healthy and malignant haematopoiesis, especially along the myeloid lineage, HRH1 lacked a relevant role in survival/proliferation and chemoresistance of AML cells, as analysed by HRH1 knockdown (KD) and pharmacological modulation. However, HRH1‐mediated signalling was critical for the activation of the differentiation process induced by several agents including all‐trans retinoic acid, establishing a role for HRH1 in myeloid differentiation. Pharmacological activation of Erk was able to partially restore differentiation capacity in HRH1 KD AML cells, suggesting that HRH1 signalling acts upstream MAPK‐Erk pathway. As an indirect consequence of our results, treatment‐related histamine release is not expected to confer a proliferative advantage in leukaemic cells.  相似文献   

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Spermiogenesis is a complex and highly ordered spermatid differentiation process that requires reorganization of cellular structures. We have previously found that Atg7 is required for acrosome biogenesis. Here, we show that autophagy regulates the round and elongating spermatids. Specifically, we found that Atg7 is required for spermatozoa flagella biogenesis and cytoplasm removal during spermiogenesis. Spermatozoa motility of atg7-null mice dropped significantly with some extra-cytoplasm retained on the mature sperm head. These defects are associated with an impairment of the cytoskeleton organization. Functional screening revealed that the negative cytoskeleton organization regulator, PDLIM1 (PDZ and LIM domain 1 [elfin]), needs to be degraded by the autophagy-lysosome-dependent pathway to facilitate the proper organization of the cytoskeleton. Our results thus provide a novel mechanism showing that autophagy regulates cytoskeleton organization mainly via degradation of PDLIM1 to facilitate the differentiation of spermatids.  相似文献   

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ABSTRACT

The molecular mechanism of autophagy in Lactoferrin (LF) induced osteoblast differentiation is not fully demonstrated. In this study, alkaline phosphatase (ALP) activity, alizarin red S staining and ELISA were used to study N-terminal propeptide of type I procollagen (PINP) expression. mRFP-GFP-LC3 adenoviruses, mono-dansylcadaverine (MDC) staining, scanning electron microscopy, and western blot analysis was employed to probe the LF induced autophagy. The interaction between autophagy receptor Neighbor of Brca1 gene (Nbr1) and pp38 was studied. 3-methyladenine (3-MA) and chloroquine (CQ) could inhibit the activity of ALP, PINP and the autophagy in LF group. LF treatment could up-regulate and down-regulate the expressions of pp38 and Nbr1with a dose-dependent manner, respectively. LF could inhibit the recognition of pp38 and Nbr1. In addition, LF can prompt Nbr1-medicated autophagy and prevent pp38 degradation by autophagy. LF can induce Nbr1-mediated autophagy and inhibit pp38 entering into autophagy flux in the physiological process of osteoblast differentiation.

Abbreviations: CQ:chloroquine;LF: Lactoferrin; 3-MA: 3-methyladenine; ALP: Alkaline phosphatase; ANOVA: Analysis of variance; CCK-8: Cell Counting Kit-8; LC3: Microtubule-associated protein light chain3; MDC: Monodansylcadaverine; Nbr1: neighbor of Brca1 gene; PINP: N-terminal propeptide of type I procollagen; PVDF: Polychlorotrifluoroethylene; pp38: phosphorylation p38; RAPA: Rapamycin; SDS: sodium dodecyl sulfate.  相似文献   

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Liu SC  Zhang ZY  Li E 《生理学报》2002,54(1):33-37
为探讨地塞米松(dexamethasone,DEX)抑制成骨细胞分化的机制,观察了不同浓度DEX对体外培养大鼠成骨细胞的碱性磷酸酶活性,骨钙素(osteocalcin,OC)合成,I型胶原蛋白表达的影响。并用RT-PCR方法检测了成骨细胞中LIM矿化蛋白1mRNA的表达量,结果显示:低浓度(10^-9mol/L)的DEX能增强碱性磷酸酶的活性、OC的分泌和I型胶原蛋白的表达;而高浓度(10^-7mol/L)的DEX对它们则起抑制作用,并下调成骨细胞正调节因子LMP-1mRNA的表达,上述结果表明,低浓度的DEX促进成骨细胞的分化;高浓度的DEX则抑制成骨细胞的分化,其抑制作用可能是通过下调LMP-1mRNA的表达而实现的。  相似文献   

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The role of extracellular signal-regulated kinase (ERK) signaling in skeletal myogenesis has been reported to be both stimulatory and inhibitory. We propose that this discrepancy may arise from the stage-specific, different roles of mitogen-activated protein kinase kinase 1 (MEK1). We found that the phosphorylated MEK1 level of differentiating C2C12 cells was low on day 1 (early-stage) and reached a maximum on days 2–3 (mid-stage). Cells treated at early stage with the MEK-specific inhibitors, PD184352 and U0126, reduced both the MHC protein level and MCK promoter activity, demonstrating that high MEK1 activity at the mid-stage is required for myogenic differentiation. In contrast, treatment with the ERK-specific inhibitors, FR180204 and ERK inhibitor I, had no effect. However, because the sustained overexpression of constitutively active MEK1 inhibits myogenic differentiation, we further analyzed the stage-specific role of MEK1 using the Tet-Off expression system. The results demonstrated that myogenic differentiation was inhibited if active MEK1 expression was induced earlier than day 1 in differentiation condition, but stimulated if induced after that, demonstrating that activated MEK1 plays differential roles depending on activation time. In addition, the induction of active MEK1 at 12 h enhanced the Id2 protein level, while the induction at 36 h resulted in reduction. Thus, MEK1 plays stage-specific and contrary roles in myogenesis, and MEK1 activated at the mid-stage promotes muscle differentiation independent of ERK.  相似文献   

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K562 cells can be used as a model of erythroid differentiation on being induced by hemin. We found that the level of annexin1 gene expression was notably increased during this indicated process. To test the hypothesis that annexin1 can regulate erythropoiesis, K562 cell clones in which annexin1 was stably increased and was knocked down by RNAi were established, respectively. With analysis by hemoglobin quantification, benzidine staining, and marker gene expression profile determination, we confirmed that hemin-induced erythroid differentiation of K562 cells was modestly stimulated by overexpression of annexin1 while it was significantly blocked by knock down of annexin1. Further studies revealed that the mechanisms of annexin1 regulation of the erythroid differentiation was partially related to the increased ERK phosphorylation and expression of p21(cip/waf), since specific inhibitor of MEK blocked the function of annexin1 in erythroid differentiation. We concluded that annexin1 exerted its erythropoiesis regulating effect by ERK pathway.  相似文献   

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Protein S-glutathionylation is a reversible post-translational modification on cysteine residues forming a mixed disulfide with glutathione. S-glutathionylation, not only protects proteins from oxidation but also regulates the functions of proteins involved in various cellular signaling pathways. In this study, we developed a method for the detection of S-glutathionylated proteins (ProSSG) using eosin-glutathione (E-GSH) and mouse glutaredoxin 1 (mGrx1). ProSSG was efficiently and specifically labeled with E-GSH to form ProSSG-E via thiol-disulfide exchange. ProSSG-E was readily luminescent allowing the detection of ProSSG with semi-quantitative determination. In addition, a deglutathionylation enzyme mGrx1 specifically released E-GSH from ProSSG-E, which increased fluorescence allowing a sensitive determination of ProSSG levels. Application of the method to the adipocyte differentiation of 3T3-L1 cells showed specific detection of ProSSG and its increase upon differentiation induction, which was consistent with the result obtained by conventional immunoblot analysis, but with greater specificity and sensitivity.  相似文献   

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