Wnt信号通路在造血干细胞自我更新和扩增中的作用

Wnt信号分子是一类在无脊椎与脊椎动物的多种组织中广泛表达且进化上高度保守的信号刺激因子,由于它们在生长、发育、代谢和干细胞调节等多种生物学过程中的重要生物学功能而被广泛重视。根据其激活的信号通路不同,Wnt分子可分为经典和非经典两类。经典类和非经典类Wnt分子分别通过激活β-catenin、Ca2+及JNK信号通路而发挥作用。近年来的研究显示,经典和非经典Wnt信号通路均在造血干细胞的自我更新和功能维持的调控中发挥关键作用。该文通过对经典和非经典Wnt信号通路的分子调控机理的探讨,对近年来有关Wnt信号通路在HSC自我更新调控中的研究进展进行了综述,对Wnt信号通路与造血微环境中其他信号通路在造血发生、维持和重建中的关系进行了讨论。     

Wnt信号通路与高血压疾病的研究进展

Wnt信号分子是一类在无脊椎与脊椎动物的多种组织中广泛表达且进化上高度保守的信号刺激分子,他们在生长、发育、代谢和干细胞调节等多种生物学过程中发挥重要作用。在健康成人的器官中Wnt信号是沉默的,但是在病理情况下Wnt信号激活。近年发现Wnt信号通路在心血管疾病的发生发展过程中扮演重要角色。本文将详细介绍Wnt信号通路,及其与高血压疾病的研究进展,试图将对Wnt信号通路的调控作为治疗高血压疾病的新的方向。     

经典Wnt信号通路对胰腺发育及其疾病发生的调控

经典Wnt信号通路是一条极其保守的信号通路,在多种组织器官发育及疾病发生过程中起重要作用,这条信号通路在胰腺中的作用近年来才逐渐被揭示.研究表明,经典Wnt信号通路在胰腺命运特化、胰腺祖细胞增殖等发育过程中起重要调控作用.另外.这条信号通路与Ⅱ型糖尿病和胰腺肿瘤的发生密切相关.本文对经典Wnt信号通路在胰腺发育及搪尿病和胰腺癌中的作用进行综述.     

经典Wnt信号通路与非小细胞肺癌潜在治疗靶点的研究新进展

经典Wnt信号通路在人类非小细胞肺癌(non-small cell lung cancer,NSCLC)的发病和病程进展中具有重要的调控作用,它与肿瘤组织的增殖、生长、代谢、侵袭和转移有着紧密联系。在NSCLC发生发展中,经典Wnt信号通路的相关蛋白表达发生较复杂的改变,并影响疾病预后,因此,研究这些相关蛋白的表达情况有助于明确NSCLC发病机制以及研究潜在治疗方法。现对经典Wnt通路中NSCLC相关蛋白表达情况和作用以及潜在治疗靶点进行了归纳。     

Wnt信号转导通路与神经发育研究进展

Wnt蛋白是一类分泌型糖蛋白家族,Wnt信号蛋白与细胞表面的多种受体相互作用,参与诸多生命过程。对神经系统发育的研究表明,Wnt信号通路在神经发生,神经祖细胞增值、分化,神经干细胞的自我更新,轴突导向等过程中起重要调控作用。多项研究已经证实,Wnt通路失调与诸多神经系统疾病有密切关系。Wnt信号通路的突变或异常,将会引起神经系统发育缺陷。然而,对Wnt非经典信号通路的研究,尤其是新受体Ryk的调控作用的认识迄今仍不全面。根据国内外相关研究,阐述了经典Wnt信号通路Wnt/β-catenin途径的同时也对Wnt/Ryk非经典信号途径这一研究新领域做了讨论。在非经典信号通路中,Ryk-ICD的剪接对于前体细胞的神经分化起重要作用。本文分析了Wnt/β-catenin和Wnt/Ryk信号通路在神经发育中的作用,有助于深入理解神经发育过程中Wnt信号通路的作用机制。然而,Ryk-ICD引导因子、分子机制等问题仍待进一步研究,而这将有利于理解神经干细胞分化机理。     

Wnt信号通路对细胞增殖的调控

Wnt信号通路是一种在进化上高度保守的信号通路,在机体细胞的生长、发育以及代谢平衡等过程中发挥重要作用。细胞增殖是生物体生长、发育和遗传的基础。许多研究发现,Wnt信号通路中关键分子的变化会促进或抑制细胞增殖。现综述Wnt信号通路的组成、调控机理以及Wnt信号通路对细胞增殖的调控,并讨论基于Wnt信号通路影响细胞增殖的理论开发治疗癌症药物的可能性。     

Wnt信号通路调控脂肪发育与代谢的研究进展

肥胖是形成Ⅱ型糖尿病和心血管疾病的重要风险因子.Wnt信号通路是调控多个细胞发育与分化的重要信号因子.本研究介绍了脂肪组织结构、脂肪细胞分化的调控因子、经典和非经典Wnt信号通路.从肥胖与糖尿病的临床观察、脂肪分化与发育、线粒体代谢与炎症反应的角度,阐述了经典和非经典Wnt信号通路对脂肪发育和代谢的影响.     

Wnt/β-catenin信号通路对靶基因转录的调控

Wnt/β-catenin信号通路又被称为经典Wnt信号通路,在早期胚胎发育、成体组织稳态维持、干细胞干性调控和肿瘤发生等过程中均发挥重要作用.经典Wnt信号通路的核心信号转导因子β-catenin与核内转录因子TCF/LEF家族成员结合后,通过募集或替换一系列协同作用因子,诱导染色质结构变化,调控Wnt信号靶基因的转录.本文将从Wnt信号靶基因转录调控的基本模式、分子机制、表观遗传学调控和意义等方面,总结近年来有关Wnt信号靶基因转录调控的研究成果,方便读者更好地理解Wnt信号通路靶基因的转录调控.     

WIF-1研究进展

WIF-1是Wnt信号通路上的拮抗物之一,可以阻断Wnt的经典通路和非经典通路。目前在人类多种肿瘤的研究发现WIF-1表达异常。WIF-1（Wnt inhibitory factor-1）,sFRP（Frizzled related protein）和CER（Cerberus）属于Wnt拮抗物家族,通过直接与Wnt蛋白相连从而阻止Wnt与受体蛋白复合物相连,使细胞质中的β-catenin由于磷酸化而不能积累,进而阻断了经典通路和非经典通路。WIF-1可能与中胚层的发生以及肿瘤细胞的生长分化有关。Wnt家族其他成员已经被证实与早期冠心病、Ⅱ型糖尿病、肥胖症、骨质疏松症等相关。因此了解WIF-1在通路上的更多信息,解释WIF-1调节Wnt信号通路的机理和过程,为疾病治疗和预防以及药物开发提供新的方法。     

Wnt/β-catenin信号通路与肝癌

肝细胞癌是常见的恶性肿瘤,其发病机制尚未完全明确。Wnt信号通路与人体内多种病理生理过程相关,其中肝癌的发生、发展可能与经典的Wnt/β-catenin信号通路密切相关。Wnt/β-catein信号通路通过表达癌症相关基因、激活肝星状细胞、调控肝干细胞行为、促进肝癌细胞侵袭转移等方式调控肝癌的发生、发展。Wnt/β-catein信号通路在肝癌发生、发展中的作用有望为肝癌研究提供新的思路。     

Nuclear beta-catenin localization is not sufficient for canonical Wnt signaling activation in human meianoma cell lines

In most cases, advanced stages of melanoma are practically incurable due to high metastatic potential of tumor cells. Multiple observations support the idea that aberrations in Wnt signaling pathway play a significant role in melanoma development and progression. Canonical Wnt signaling activation results in stabilization and accumulation of the major effector molecule called beta-catenin. Mutations promoting beta-catenin stabilization and, thereby, activation of canonical Wnt signaling pathway are frequently found in different cancers, but rarely observed in melanomas. Nevertheless, beta-catenin nuclear and cytoplasmic accumulation is the feature of many human melanoma cell lines and original tumors. That is why, the aim of the investigation was to elucidate the relation between beta-catenin intracellular localization and activity status of Wnt signaling pathway in human melanoma cell lines. Ten human melanoma cell lines were characterized on the basis of the following parameters: canonical Wnt ligand expression, intracellular beta-catenin localization, and activity status of canonical Wnt signaling pathway. Here, it has been demonstrated that nuclear localization of beta-catenin does not always correspond to active status canonical Wnt signaling pathway. Moreover, in the majority of cell lines with nuclear beta-catenin canonical Wnt signaling can't be activated by exogenous expression of an appropriate ligand. Human melanoma cell lines differ in activity of canonical Wnt signaling pathway as well as in mechanisms of its regulation. Therefore, the pathway-targeted potential antineoplastic therapy requires the formation of a "molecular pattern of cancer" for localization of the defect in Wnt signaling cascade in the each case.     

Wnt/beta-catenin 通路在成骨细胞中的作用

Wnt信号通路包括经典通路和非经典通路两种,其中Wnt经典通路又称为Wnt/β-catenin通路,其在成骨细胞的分化、增殖过程中发挥这重要的作用。Wnt信号通路实现过程中有多种因子参与,包括Wnt蛋白、β-catenin、蛋白激酶GSK-3β以及APC蛋白等多种。Wnt蛋白家族是由19种Wnt蛋白组成的,主要分为经典Wnt蛋白和非经典Wnt蛋白,其本质是一系列高度保守的分泌性糖蛋白,并且不同的Wnt蛋白对成骨细胞发挥着不同的作用,其中经典Wnt蛋白通过经典Wnt信号作用于成骨细胞对成骨细胞的增殖、分化有着重要的影响。本综述通过对Wnt经典信号通路过程中的多种因子与成骨细胞分化、增殖的关系进行分析总结,了解Wnt/β-catenin通路对成骨细胞的作用。     

Differential activation of canonical Wnt signaling determines cranial sutures fate: A novel mechanism for sagittal suture craniosynostosis

Premature closure of cranial sutures, which serve as growth centers for the skull vault, result in craniosynostosis. In the mouse posterior frontal (PF) suture closes by endochondral ossification, whereas sagittal (SAG) remain patent life time, although both are neural crest tissue derived. We therefore, investigated why cranial sutures of same tissue origin adopt a different fate. We demonstrated that closure of the PF suture is tightly regulated by canonical Wnt signaling, whereas patency of the SAG suture is achieved by constantly activated canonical Wnt signaling. Importantly, the fate of PF and SAG sutures can be reversed by manipulating Wnt signaling. Continuous activation of canonical Wnt signaling in the PF suture inhibits endochondral ossification and therefore, suture closure, In contrast, inhibition of canonical Wnt signaling in the SAG suture, upon treatment with Wnt antagonists results in endochondral ossification and suture closure. Thus, inhibition of canonical Wnt signaling in the SAG suture phenocopies craniosynostosis. Moreover, mice haploinsufficient for Twist1, a target gene of canonical Wnt signaling which inhibits chondrogenesis, have sagittal craniosynostosis. We propose that regulation of canonical Wnt signaling is of crucial importance during the physiological patterning of PF and SAG sutures. Importantly, dysregulation of this pathway may lead to craniosynostosis.     

Nuclear β-catenin localization is not sufficient for canonical Wnt signaling activation in human melanoma cell lines

In most cases, advanced stages of melanoma are practically incurable due to high metastatic potential of tumor cells. Multiple observations support the idea that aberrations in the Wnt signaling pathway play a significant role in melanoma development and progression. Canonical Wnt signaling activation results in stabilization and accumulation of the major effector molecule called & gb-catenin. Mutations promoting & gb-catenin stabilization and, thereby, activation of canonical Wnt signaling pathway are frequently found in different cancers but rarely observed in melanomas. Nevertheless, & gb-catenin nuclear and cytoplasmic accumulation is the feature of many human melanoma cell lines and original tumors. That is why the aim of the investigation was to elucidate the relation between & gb-catenin intracellular localization and activity status of Wnt signaling pathway in human melanoma cell lines. Ten human melanoma cell lines were characterized on the basis of the following parameters: canonical Wnt ligand expression, intracellular & gb-catenin localization and activity status of canonical Wnt signaling pathway. Here, it has been demonstrated that nuclear localization of & gb-catenin does not always correspond to active status of canonical Wnt signaling pathway. Moreover, in the majority of cell lines with nuclear & gb-catenin, canonical Wnt signaling cannot be activated by exogenous expression of an appropriate ligand. Human melanoma cell lines differ in activity of canonical Wnt signaling pathway as well as in mechanisms of its regulation. Therefore, pathway-targeted potential antineoplastic therapy requires the formation of a & ldmolecular pattern of cancer” for localization of the defect in Wnt signaling cascade in each case.     

The roles of canonical and non-canonical Wnt signaling in human de-differentiated articular chondrocytes

Osteoarthritis is the most prevalent form of arthritis in the world and it is becoming a major public health problem. Osteoarthritic chondrocytes undergo morphological and biochemical changes that lead to de-differentiation. The involvement of signaling pathways, such as the Wnt pathway, during cartilage pathology has been reported. Wnt signaling regulates critical biological processes. Wnt signals are transduced through at least three intracellular signaling pathways including the canonical Wnt/β-catenin pathway, the Wnt/Ca2 + pathway and the Wnt/planar cell polarity pathway. We investigated the involvement of the Wnt canonical and non-canonical pathways in human articular chondrocyte de-differentiation in vitro. Human articular chondrocytes were cultured through four passages with no treatment, or with sFRP3 treatment, an inhibitor of Wnt pathways, or with DKK1 treatment, an inhibitor of the canonical pathway. Chondrocyte-secreted markers and Wnt pathway components were analyzed using western blotting and qPCR. Inhibition of the Wnt pathway showed that the canonical Wnt signaling probably is responsible for inhibition of collagen II expression, activation of metalloproteinase 13 expression and regulation of Wnt7a and c-jun expression during chondrocyte de-differentiation in vitro. Our results also suggest that expressions of eNOS, Wnt5a and cyclinE1 are regulated by non-canonical Wnt signaling.     

Wnt‐induced activation of glucose metabolism mediates the in vivo neuroprotective roles of Wnt signaling in Alzheimer disease

Dysregulated Wnt signaling is linked to major neurodegenerative diseases, including Alzheimer disease (AD). In mouse models of AD, activation of the canonical Wnt signaling pathway improves learning/memory, but the mechanism for this remains unclear. The decline in brain function in AD patients correlates with reduced glucose utilization by neurons. Here, we test whether improvements in glucose metabolism mediate the neuroprotective effects of Wnt in AD mouse model. APPswe/PS1dE9 transgenic mice were used to model AD, Andrographolide or Lithium was used to activate Wnt signaling, and cytochalasin B was used to block glucose uptake. Cognitive function was assessed by novel object recognition and memory flexibility tests. Glucose uptake and the glycolytic rate were determined using radiotracer glucose. The activities of key enzymes of glycolysis such as hexokinase and phosphofructokinase, Adenosine triphosphate (ATP)/Adenosine diphosphate (ADP) levels and the pentose phosphate pathway and activity of glucose‐6 phosphate dehydrogenase were measured. Wnt activators significantly improved brain glucose utilization and cognitive performance in transgenic mice. Wnt signaling enhanced glucose metabolism by increasing the expression and/or activity of hexokinase, phosphofructokinase and AMP‐activated protein kinase. Inhibiting glucose uptake partially abolished the beneficial effects of Wnt signaling on learning/memory. Wnt activation also enhanced glucose metabolism in cortical and hippocampal neurons, as well as brain slices derived from APPswe/PS1E9 transgenic mice. Combined, these data provide evidence that the neuroprotective effects of Wnt signaling in AD mouse models result, at least in part, from Wnt‐mediated improvements in neuronal glucose metabolism.