c-Abl在DNA损伤反应中的功能

非受体酪氨酸激酶c-Abl在正常生理及病理条件下具有多种生物学功能。当电离辐射、顺铂、丝裂霉素C等DNA损伤诱导剂诱导DNA损伤反应后,c-Abl可参与DNA损伤反应后的细胞周期调控、基因重组修复及细胞凋亡调控等,进而决定细胞在DNA损伤反应条件下的状态。简要介绍了c-Abl在DNA损伤反应中的作用及其进展。     

Hippo通路在神经发育和神经系统疾病中的功能

Hippo通路是一个调控组织器官大小、细胞增殖、分化和凋亡的高度保守的信号通路.我们研究了氧化压力条件下Hippo通路在神经细胞中的作用,并发现哺乳动物STE20样的丝-苏氨酸蛋白激酶(MST1)可参与氧化应激诱导的神经细胞凋亡,其上游受非受体酪氨酸激酶c-Abl的调控.近期,我们研究发现MST1参与脑缺血引起的神经炎症,还发现Yes相关蛋白1(YAP)参与神经干细胞的自我更新.本文将介绍Hippo通路在中枢神经系统疾病和神经发育中的作用和机制研究的相关进展.     

综述: Hippo通路在神经发育和神经系统疾病中的功能

Hippo通路是一个调控组织器官大小、细胞增殖、分化和凋亡的高度保守的信号通路.我们研究了氧化压力条件下Hippo通路在神经细胞中的作用,并发现哺乳动物STE20样的丝-苏氨酸蛋白激酶(MST1)可参与氧化应激诱导的神经细胞凋亡,其上游受非受体酪氨酸激酶c-Abl的调控.近期,我们研究发现MST1参与脑缺血引起的神经炎症,还发现Yes相关蛋白1(YAP)参与神经干细胞的自我更新.本文将介绍Hippo通路在中枢神经系统疾病和神经发育中的作用和机制研究的相关进展.     

c-Abl与应激损伤调控

非受体酪氨酸激酶c-Abl广泛表达于人和哺乳动物等的细胞中并受到严格调控,通过蛋白之间相互作用、与DNA相互作用及其酪氨酸激酶活性在一系列的重要生命活动中发挥调节作用。在应激损伤反应如DNA损伤反应中．c-Abl的Ser^465被ATM和DNA-PK磷酸化而激活,通过与Rad51、p53和p73等分子的相互作用参与DNA重组修复、细胞周期和细胞凋亡等的调控,不同信号途径之间的平衡决定细胞的生存和死亡。     

PI3K/Akt信号通路相关的生物学调控机制研究进展

PI3K/Akt信号通路是由酶联受体介导的信号转导通路,该通路不仅参与多种生长因子、细胞因子和细胞外基质等的信号转导,同时还参与细胞增殖、分化、凋亡和葡萄糖转运等多种细胞功能的调节,特别是在细胞凋亡、细胞存活以及调控细胞糖代谢等方面具有重要作用。本研究综述了PI3K-Akt信号通路的结构组成、通路活化、通信过程、调控机制及其生物学功能等方面的研究进展,为进一步研究PI3K/Akt信号通路的生物学调控作用机制提供启示。     

GSK-3β在相关疾病中的作用及致病机制的研究进展

糖原合成酶激酶-3(GSK-3)是一种存在于所有真核细胞质中的丝氨酸/苏氨酸蛋白激酶,分为α和β两种亚型。研究显示GSK-3β在调控糖代谢,细胞炎症反应,神经及心脏功能和生殖功能中具有重要作用。其致病机制主要是通过磷酸化不同信号通路关键酶从而参与细胞新陈代谢,增殖,衰老,凋亡等生理活动的调控过程。本文主要对GSK-3β可能导致的多种疾病及其发病机制进行综述。     

细胞质内信号分子的核转位及其机制

细胞外信号通过受体及细胞内信号转导引起细胞生长,增殖,分化,凋亡等细胞核反应。进入细胞质内的信号分子及其活化产物必须经过细胞核膜上的核孔复合体（ＮＰＣ）,在核定位信号的介导下,由特异性的载体转运入核,该过程涉及小分子的ＧＴＰａｓｅ Ｒａｎ蛋白及多种可溶性因子。本文简要综述细胞质内信号分子通过核膜向细胞核内转运的过程及其调控机制。     

早幼粒白血病蛋白核体与病毒感染

早幼粒白血病蛋白核体（promyelocytic leukaemia nuclear bodies,PML-NBs）是哺乳动物细胞中普遍存在的一种动态的细胞核亚结构,参与DNA损伤与修复、细胞衰老与凋亡、基因表达调控以及肿瘤发生与抑制等多种重要的细胞活动。研究表明,PML-NBs也是多种病毒入侵细胞的作用靶点。PML-NBs通过介导细胞固有免疫反应或者作为细胞干扰素信号通路元件参与宿主细胞的抗病毒防御活动。该文以几种DNA和RNA病毒为例,综述了在病毒感染过程中PML-NBs与病毒的相互作用以及这些相互作用的功能意义,从而揭示PML-NBs在抵御病毒感染和免疫反应中的重要作用,并提出运用病毒单分子实时示踪（Single-virus Tracking）这一新技术深入研究PML-NBs在病毒感染中作用的可行性。     

PARP-1／AIF介导的细胞凋亡

PARP-1／AIF通路介导的非caspase依赖性细胞凋亡多见于缺血再灌注或某些药物引起的神经细胞死亡。PARP-1定位于细胞核,参与细胞内多种生理活动。广泛的DNA损伤引起PARP-1过度激活,进而使线粒体蛋白AIF转位至细胞核,作为DNA内切酶引发染色质凝集、DNA片段化和细胞死亡。最近,对该通路信号转导和调控机制的研究取得了快速的进展。     

三基序蛋白27的生理意义及其在肿瘤发生发展中的作用

三基序蛋白27(tripartite motif 27,TRIM27)是一种E3泛素连接酶，在细胞核、胞质溶胶和内体中均有分布，广泛存在于多种细胞中。TRIM27还具有转录抑制活性以及SUMO E3连接酶活性。TRIM27参与调控机体多种正常的生理过程：例如作为转录调控蛋白质促进减数分裂过程，与生殖过程密切相关；通过增强胱天蛋白酶3(cysteine-containing aspartate-specific protease-3,caspase-3)活性诱导正常细胞凋亡过程的发生；不仅可以抑制由IκB激酶(IkappaB kinase, IKK)家族成员介导的NF-κB的激活，还能通过泛素化降解NF-κB抑制剂Iκbα,进而参与NF-κB信号通路，在先天免疫中发挥重要调控作用；通过激活STAT3信号通路参与多种炎症疾病的发生。最新研究表明，TRIM27还参与了癌症进程关键信号通路，例如PI3K/AKT,Wnt/β-catenin等，从而促进非小细胞肺癌，结直肠癌和肝癌等多种常见癌症细胞的增殖、侵袭和转移能力，抑制它们凋亡过程的发生以及抑制卵巢癌细胞的细胞周期停滞。同时，TRIM27作...     

c-Abl is involved in high glucose-induced apoptosis in embryonic E12.5 cortical neural progenitor cells from the mouse brain

Hyperglycemia causes direct apoptosis of neural progenitor cells (NPCs) in diabetic-induced neural tube defects in embryos. However, the underlying mechanisms are poorly understood. The present study is aimed to investigate the specific cellular proteins that may be involved in NPCs apoptosis as well as mechanisms by which the proteins regulate the oxidative stress-induced NPCs apoptosis. Our present results have shown that the expression of c-Abl was up-regulated in NPCs exposed to high glucose in vitro . The increased c-Abl was localized mainly in the nucleus. High glucose also induced an increase in nuclear p53 protein levels and the p53-c-Abl complex in NPCs. Administration of reactive oxygen species scavengers decreased the protein level of c-Abl, p53 and NPCs apoptosis. Inhibition of c-Abl reduced NPCs apoptosis and the nuclear protein level of p53 in response to high glucose. These results demonstrate that c-Abl is involved in the reactive oxygen species-activated apoptotic pathways in NPCs apoptosis. Inhibition of c-Abl may protect NPCs against insults induced by high glucose via the modulation of NPCs apoptotic machinery.     

Aph2, a protein with a zf-DHHC motif,interacts with c-Abl and has pro-apoptotic activity

c-Abl is a non-receptor tyrosine kinase implicated in DNA damage-induced cell death and in growth factor receptor signaling. To further understand the function and regulation of c-Abl, a yeast two-hybrid screen was performed to identify c-Abl-interacting proteins. Here we report the identification of Abl-philin 2 (Aph2), encoding a novel protein with a unique cysteine-rich motif (zf-DHHC) and a 53-amino acid stretch sharing homology with the creatine kinase family. The zf-DHHC domain is highly conserved from yeast to human. Two proteins containing this motif, Akr1p and Erf2p, have been characterized in Saccharomyces cerevisiae, both implicated in signaling pathways. Deletion analysis by two-hybrid assays revealed that the N-terminal portion of Aph2 interacts with the C terminus of c-Abl. Aph2 was demonstrated to interact with c-Abl by co-immunoprecipitation assays. Aph2 is expressed in most tissues tested and is localized in the cytoplasm, mainly in the endoplasmic reticulum (ER). The sequences required for ER location reside in the N terminus and the zf-DHHC motif of Aph2. It has been reported that a portion of c-Abl is localized in the ER. We demonstrate here that Aph2 and c-Abl are co-localized in the ER region. Overexpression of Aph2 leads to apoptosis as justified by TUNEL assays, and the induction of apoptosis requires the N terminus. Co-expression of c-Abl and Aph2 had a synergistic effect on apoptosis induction and led to a decreased expression of both proteins, suggesting either that these two proteins are mutually down-regulated or that cells expressing both c-Abl and Aph2 rapidly disappeared from the culture. These results suggest that Aph2 may be involved in ER stress-induced apoptosis in which c-Abl plays an important role.     

The c-Abl tyrosine kinase is regulated downstream of the B cell antigen receptor and interacts with CD19

c-Abl is a nonreceptor tyrosine kinase that we have recently linked to growth factor receptor signaling. The c-Abl kinase is ubiquitously expressed and localizes to the cytoplasm, plasma membrane, cytoskeleton, and nucleus. Thus, c-Abl may regulate signaling processes in multiple subcellular compartments. Targeted deletion or mutation of c-Abl in mice results in a variety of phenotypes, including splenic and thymic atrophy and lymphopenia. Additionally, lymphocytes isolated from specific compartments of c-Abl mutant mice have reduced responses to a variety of stimuli and an increased susceptibility to apoptosis following growth factor deprivation. Despite these observations, little is known regarding the signaling mechanisms responsible for these phenotypes. We report here that splenic B cells from c-Abl-deficient mice are hyporesponsive to the proliferative effects of B cell Ag receptor (BCR) stimulation. The c-Abl kinase activity and protein levels are elevated in the cytosol following activation of the BCR in B cell lines. We show that c-Abl associates with and phosphorylates the BCR coreceptor CD19, and that c-Abl and CD19 colocalize in lipid membrane rafts. These data suggest a role for c-Abl in the regulation of B cell proliferation downstream of the BCR, possibly through interactions with CD19.     

Targeting of the c-Abl tyrosine kinase to mitochondria in endoplasmic reticulum stress-induced apoptosis

The ubiquitously expressed c-Abl tyrosine kinase localizes to the nucleus and cytoplasm. Using confocal microscopy, we demonstrated that c-Abl colocalizes with the endoplasmic reticulum (ER)-associated protein grp78. Expression of c-Abl in the ER was confirmed by immunoelectron microscopy. Subcellular fractionation studies further indicate that over 20% of cellular c-Abl is detectable in the ER. The results also demonstrate that induction of ER stress with calcium ionophore A23187, brefeldin A, or tunicamycin is associated with translocation of ER-associated c-Abl to mitochondria. In concert with targeting of c-Abl to mitochondria, cytochrome c is released in the response to ER stress by a c-Abl-dependent mechanism, and ER stress-induced apoptosis is attenuated in c-Abl-deficient cells. These findings indicate that c-Abl is involved in signaling from the ER to mitochondria and thereby the apoptotic response to ER stress.     

A positive role for c-Abl in Atm and Atr activation in DNA damage response

DNA damage triggers Atm- and/or Atr-dependent signaling pathways to control cell cycle progression, apoptosis, and DNA repair. However, how Atm and Atr are activated is not fully understood. One of the downstream targets of Atm is non-receptor tyrosine kinase c-Abl, which is phosphorylated and activated by Atm. The current view is that c-Abl relays pro-apoptotic signals from Atm to p73 and p53. Here we show that c-Abl deficiency resulted in a broad spectrum of defects in cell response to genotoxic stress, including activation of Chk1 and Chk2, activation of p53, nuclear foci formation, apoptosis, and DNA repair, suggesting that c-Abl might also act upstream of the DNA damage-activated signaling cascades in addition to its role in p73 and p53 regulation. Indeed, we found that c-Abl is required for proper activation of both Atm and Atr. c-Abl is bound to the chromatin and shows enhanced interaction with Atm and Atr in response to DNA damage. c-Abl can phosphorylate Atr on Y291 and Y310 and this phosphorylation appears to have a positive role in Atr activation under genotoxic stress. These findings suggest that Atm-mediated c-Abl activation in cell response to double-stranded DNA breaks might facilitate the activation of both Atm and Atr to regulate their downstream cellular events.     

c-Abl: activation and nuclear targets

The c-Abl tyrosine kinase and its transforming variants have been implicated in tumorigenesis and in many important cellular processes. c-Abl is localized in the nucleus and the cytoplasm, where it plays distinct roles. The effects of c-Abl are mediated by multiple protein-protein and protein-DNA interactions and its tyrosine kinase domain. At the biochemical level, the mechanism of c-Abl kinase activation and the identification of its target proteins and cellular machineries have in part been solved. However, the phenotypic outcomes of these molecular events remained in large elusive. c-Abl has been shown to regulate the cell cycle and to induce under certain conditions cell growth arrest and apoptosis. In this respect the interaction of c-Abl with p53 and p73 has attracted particular attention. Recent findings have implicated c-Abl in an ionizing irradiation signaling pathway that elicits apoptosis. In this pathway p73 is an important immediate downstream effector. Here I review the current knowledge about these nuclear processes in which c-Abl is engaged and discuss some of their possible implications on cell physiology. Cell Death and Differentiation (2000) 7, 10 - 16.     

Role of c-Abl in directing metabolic versus mitogenic effects in insulin receptor signaling

c-Abl is a cytoplasmic tyrosine kinase involved in several signal transduction pathways. Here we report that c-Abl is involved also in insulin receptor signaling. Indeed, c-Abl tyrosine kinase is activated upon insulin stimulation. Inhibition of c-Abl tyrosine kinase by STI571 attenuates the effect of insulin on Akt/GSK-3beta phosphorylation and glycogen synthesis, and at the same time, it enhances the effect of insulin on ERK activation, cell proliferation, and migration. This effect of STI571 is specific to c-Abl inhibition, because it does not occur in Abl-null cells and is restored in c-Abl-reconstituted cells. Numerous evidences suggest that focal adhesion kinase (FAK) is involved in mediating this c-Abl effect. First, anti-phosphotyrosine blots indicate that c-Abl tyrosine kinase activation is concomitant with FAK dephosphorylation in response to insulin, whereas c-Abl inhibition is accompanied by FAK phosphorylation in response to insulin, a response similar to that observed with IGF-I. Second, the c-Abl effects on insulin signaling are not observed in cells devoid of FAK (FAK(-/-) cells). Taken together these results suggest that c-Abl activation by insulin, via a modification of FAK response, may play an important role in directing mitogenic versus metabolic insulin receptor signaling.     

High glucose induces apoptosis in embryonic neural progenitor cells by a pathway involving protein PKCδ

Diabetic-induced neural tube defects in embryos are caused by apoptosis of neural progenitor cells (NPCs); however, the underlying mechanisms are poorly understood. The present study is aimed to investigate the specific cellular proteins that may be involved in apoptosis of NPCs. We show here that hyperglycemia-induced apoptosis of NPCs was through a PKCδ-dependent mechanism. Tyrosine phosphorylation of PKCδ was required for PKCδ binding to c-Abl in the cytoplasm, and inhibition of c-Abl by STI571 or knock-down of c-Abl by RNAi decreased the phosphorylation of PKCδ. Moreover, translocation of PKCδ and c-Abl complex from the cytoplasm to the nucleus, was blocked by down-regulation of PKCδ or c-Abl. Furthermore, we found that interaction of PKCδ and c-Abl played a crucial role in p53 accumulation in the nucleus, which was linked to the apoptosis of NPCs in response to high glucose.