Notch信号途径及其调控

Notch是一个进化上十分保守的跨膜受体蛋白家族,对无脊椎动物和脊椎动物发育过程中的细胞命运决定起重要作用。一条重要的Notch信号途径涉及Notch的“三步蛋白质水解”活化。许多相关分子和体内生化过程参与Notch信号途径调控。调控发生在不同水平,包括Notch-配体互作、受体和配体的运输、泛素化降解等。现就Notch受体、Notch信号途径及其所受的不同水平的调控进行综述。     

Notch的结构、功能和相关信号通路

Notch是广泛存在于细胞表面介导细胞间信号传递的一类高度保守的受体蛋白。Notch信号通路是通过细胞间相互作用来调节生物体生长发育的一个十分保守的信号通路。Notch信号通路在脊椎动物和无脊椎动物的发育过程中,对细胞命运的决定、神经系统的发育、器官的形成及体节的发生都有重要的作用。特别是在免疫系统和肿瘤发生中也起着极为重要的作用。目前,Notch信号已经成为发育生物学、细胞生物学、免疫学及血液学等多个领域的研究热点之一。本文就Notch信号通路的组成、调节作用机制及该通路与个体发育之间的联系作一综述。     

Notch信号转导与调控

Notch是一个进化上十分保守的跨膜受体蛋白家族,它可以通过与表达配体的相邻细胞间的相互作用转导信号,从而决定动物系统发育过程中多种细胞的“命运”.Notch信号转导过程包括Notch受体与配体的结合、Notch受体的酶切活化、可溶性NICD转移至细胞核并与CSL DNA结合蛋白相互作用,从而调控靶基因的表达.Notch活性水平、时间和空间分布受到包括配体、蛋白质转运、泛素化降解等多水平内源性和外源性诱导因素的调节.系统介绍了Notch信号转导通路的分子组成、Notch信号激活的生化机制、Notch信号的多水平调节以及与部分相关疾病的关系.     

Notch信号途径对T细胞分化发育及细胞因子的影响

Notch是一个进化上十分保守的跨膜受体蛋白家族,它可以通过局部细胞间相互作用,调控机体的生长发育过程.近年来研究发现,Notch及其介导的信号转导与免疫系统也存在着密切的关系,从多个方面参与T细胞发育及功能的调控,包括T细胞的活化和增殖,以及细胞因子分泌.这说明Notch信号途径在免疫系统发育和成熟的免疫细胞功能调节中具有重要的作用.     

Notch信号通路与肺纤维化

Notch信号通路是在进化上非常保守的单次跨膜信号受体蛋白家族,广泛表达于脊椎动物与无脊椎动物中,主要由Notch受体、Notch配体及细胞内效应分子CSL蛋白组成。Notch信号通路是多种组织和器官早期发育所必需的细胞间调节信号,参与对细胞增殖、分化、凋亡的调控。近年的研究表明,Notch信号通路参与肺纤维化的发生发展,阻断或激活这一途径可以影响肺纤维化的进展,本文就Notch信号通路与肺纤维化的关系的研究进展做一综述。     

Notch信号途径与肿瘤血管发生

Notch信号途径广泛存在于无脊椎和哺乳动物体内,与肿瘤血管的萌发,尖端细胞的选择、血管分支的出现、脉管系统的成熟、以及血管损伤后修复等多个阶段均存在密切的关系.在血管发生过程中Notch信号途径主要受到VEGFs的调节,通过发挥抑制作用减少尖端细胞的数量和脉管分支的出现.对Notch信号途径的研究有可能成为未来肿瘤血管抑制治疗的新靶点.本文就Notch信号途径及与肿瘤血管发生之间的关系做一综述.     

Notch信号及其对T细胞发育和分化的调节

哺乳动物Notch蛋白包括四种(Notchl～Notch4),其配体分为两个家族:Jagged家族(Jaggedl,Jagged2)和Delta样家族(DLL1,DLL3,DLL4).Notch信号途径涉及一些蛋白质裂解过程,随后反式作用因子RBP-J及协同激活因子MAML等参与,最终导致靶基因的转录.在早期T细胞发育过程中起关键作用,还调节外周T细胞的活化增殖以及诱导Th细胞亚群的分化.Notch信号途径对转录因子GATA-3激活而诱导的Th2细胞分化非常重要.     

Notch在乳腺癌发病中的作用研究进展

乳腺癌是全球女性最常见的恶性肿瘤之一。Notch广泛存在于大部分生物中,高度保守,通过相邻细胞间的相互作用,调控细胞的增殖、侵袭、衰老和凋亡,以及血管生成等生理过程,扩大并固化细胞间的分子差异,最终决定细胞命运,影响器官形成和形态发生。目前的研究发现,Notch异常激活可引起乳腺癌的发生,而且Notch信号途经受多种分子和其他信号通路的调节。因此,依据Notch信号在乳腺癌中的作用及其调控机制,进一步探讨相关的靶向治疗策略,将为临床治疗乳腺癌提供新的思路与方向。本文对Notch在乳腺癌中的最新研究进展进行综述。     

Notch家族4个蛋白质对人胰腺癌细胞HPAC中YY1和EGFR表达的影响

Notch信号通路是肿瘤形成过程中一种重要的信号通路,其中心分子为Notch受体.Notch受体为细胞膜上的单次跨膜蛋白,介导细胞间信号转导,哺乳动物细胞内包括Notch1、Notch2、Notch3和Notch4的4个成员.Notch家族4个蛋白质在结构和功能上存在差异.前期研究显示,Notch1信号通路与转录因子YY1(YING-YANG 1)、表皮生长因子受体(EGFR)间存在调控作用.本研究在人胰腺癌细胞HPAC中,采用RNA干扰技术,分别降低细胞中Notch家族4个蛋白质的表达,检测YY1和EGFR在m RNA和蛋白质水平上的表达;并构建相应的激活形式的Notch受体——Notch胞内结构域(Notch intracellular domain,NICD)真核表达质粒,在HPAC细胞中分别过表达4种NICD,检测其对YY1和EGFR表达水平的影响.结果显示,降低细胞中Notch1或Notch3的表达,均使HPAC细胞中EGFR m RNA和蛋白质水平升高(P0.05),而降低Notch2和Notch4后,EGFR m RNA和蛋白质水平没有改变(P0.05).分别降低4个Notch的表达,对YY1的蛋白质和m RNA表达水平均没有改变(P0.05).在HPAC细胞中过表达N1ICD和N3ICD后,YY1和EGFR的蛋白质水平降低(P0.05),而过表达N2ICD和N4ICD后,YY1和EGFR蛋白质水平没有改变(P0.05).分别过表达4种NICD均没有改变YY1和EGFR的m RNA表达水平(P0.05).初步得出结论是,在HPAC细胞中,Notch信号通路经Notch1和Notch3影响EGFR的表达.Notch1和Notch3对EGFR的表达可能具有负调控作用.在Notch1和Notch3过度激活时,这种调控作用通过YY1介导.本文可为深入研究Notch信号通路对胰腺癌发生发展的作用机制提供有意义的参考.     

Notch信号通路在先天免疫和炎症中的作用

Notch信号通路是高度保守的信号传导途径,在无脊椎动物和有脊椎动物中均有表达,并在发育过程中起着至关重要的作用。在免疫系统中,Notch信号通路在中枢和外周淋巴器官调节T和B细胞的发育。已有研究报道了其在淋巴细胞发育中的作用,但在髓系的发育和功能中作用鲜为人知,尤其在急、慢性炎症中。文章将描述Notch信号通路在先天免疫和炎症反应中起关键调节作用,探讨其在炎症性疾病发病机制和治疗中的潜在作用。     

The intracellular form of notch blocks transforming growth factor beta-mediated growth arrest in Mv1Lu epithelial cells

Notch signaling influences a variety of cell fate decisions during development, and constitutive activation of the pathway can provoke unbridled cell growth and cancer. The mechanisms by which Notch affects cell growth are not well established. We describe here a novel link between Notch and cell cycle control. We found that Mv1Lu epithelial cells harboring an oncogenic form of Notch (NICD) are resistant to the cell cycle-inhibitory effects of transforming growth factor beta (TGF-beta). NICD did not affect TGF-beta signaling per se but blocked induction of the Cdk inhibitor p15(INK4B). c-Myc, whose down-regulation by TGF-beta is required for p15(INK4B) induction, remained elevated in the NICD-expressing cells. c-Myc expression was also maintained in low serum, indicating that Notch's effects on c-Myc are not specific to TGF-beta. Our results are consistent with a model in which a strong Notch signal indirectly deregulates c-Myc expression and thereby renders Mv1Lu epithelial cells resistant to growth-inhibitory signals.     

过表达ER恢复雌激素对子宫内膜癌KLE细胞中Notch信号通路的调控

目的：通过观察雌激素对子宫内膜癌KLE细胞中Notch信号通路的影响,探讨过表达雌激素核受体（estrogenreceptor,ER）是否可以恢复雌激素对Notch信号通路的调控作用,继而调节细胞增殖活性。方法：MTT检测雌激素及Notch信号通路对细胞增殖活性的影响;RT．PCR及Westem．blotting检测雌激素及Notch通路抑制剂DAPT对Notch表达的影响;质粒的抽提及转染使KLE细胞中的雌激素核受体ER过表达。结果：雌激素呈剂量依赖效应促进KLE细胞的增殖活性,其中以雌激素浓度为1．0×10-9M时最明显（相对于对照组为1．25±0．026,P〈0．05）;抑制Notch信号通路的表达可以明显下调KLE细胞的增殖活性（0．76±0．02,P〈0．05）;在KLE细胞中,雌激素对Notch的表达没有明显的调控作用,但是将其雌激素核受体过表达后,雌激素可明显上调Notch的表达,并显著促进细胞的增殖活性（1．24±0．02,P〈0．05）。结论：在ER阴性的子宫内膜癌细胞中过表达ER,可以恢复雌激素对Notch信号通路的调控,从而进一步的调控细胞增殖活性。     

HES6 promotes prostate cancer aggressiveness independently of Notch signalling

Notch signalling is implicated in the pathogenesis of a variety of cancers, but its role in prostate cancer is poorly understood. However, selected Notch pathway members are overrepresented in high‐grade prostate cancers. We comprehensively profiled Notch pathway components in prostate cells and found prostate cancer‐specific up‐regulation of NOTCH3 and HES6. Their expression was particularly high in androgen responsive lines. Up‐ and down‐regulating Notch in these cells modulated expression of canonical Notch targets, HES1 and HEY1, which could also be induced by androgen. Surprisingly, androgen treatment also suppressed Notch receptor expression, suggesting that androgens can activate Notch target genes in a receptor‐independent manner. Using a Notch‐sensitive Recombination signal binding protein for immunoglobulin kappa J region (RBPJ) reporter assay, we found that basal levels of Notch signalling were significantly lower in prostate cancer cells compared to benign cells. Accordingly pharmacological Notch pathway blockade did not inhibit cancer cell growth or viability. In contrast to canonical Notch targets, HES6, a HES family member known to antagonize Notch signalling, was not regulated by Notch signalling, but relied instead on androgen levels, both in cultured cells and in human cancer tissues. When engineered into prostate cancer cells, reduced levels of HES6 resulted in reduced cancer cell invasion and clonogenic growth. By molecular profiling, we identified potential roles for HES6 in regulating hedgehog signalling, apoptosis and cell migration. Our results did not reveal any cell‐autonomous roles for canonical Notch signalling in prostate cancer. However, the results do implicate HES6 as a promoter of prostate cancer progression.     

泛素连接酶对Notch信号途径的调节作用

Noah信号途径是生物进化过程中高保守的信号通路,对细胞的定向发育及成熟起到决定性的作用。Notch信号途径受到多种分子机制的严格调控。近年来,多项研究均突出了泛素化在调控Noah信号途径活性中的重要性。本文就四种E3泛素连接酶Su（dx）Itch、Sel-10、LNX以及Neuralized对于调控Noah受体及Notch信号途径配体的研究现况作一综述。     

SEPT4 is regulated by the Notch signaling pathway

Notch receptor-mediated signaling is an evolutionarily conserved pathway that regulates diverse developmental processes and its dysregulation has been implicated in a variety of developmental disorders and cancers. Notch functions in these processes by activating expression of its target genes. Septin 4 (SEPT4) is a polymerizing GTP-binding protein that serves as scaffold for diverse molecules and is involved in cell proliferation and apoptosis. After activation of the Notch signal, the expression of SEPT4 is up-regulated and cell proliferation is inhibited. When the Notch signal is inhibited by the CSL (CBF1/Su(H)/Lag-1)-binding-domain-negative Mastermind-like protein 1, the expression of SEPT4 is down-regulated, proliferation and colony formation of cells are promoted, but cell adhesion ability is decreased. Nevertheless, the SEPT4 expression is not affected after knock-down of CSL. Meanwhile, if SEPT4 activity is inhibited through RNA interference, the protein level and activity of NOTCH1 remains unchanged, but cell proliferation is dysregulated. This indicates that SEPT4 is a Notch target gene. This relationship between Notch signaling pathway and SEPT4 offers a potential basis for further study of developmental control and carcinogenesis.     

Notch signaling controls proliferation through cell-autonomous and non-autonomous mechanisms in the Drosophila eye

During Drosophila eye development, localized Notch signaling at the dorsal ventral (DV)-midline promotes growth of the entire eye field. This long-range action of Notch signaling may be mediated through the diffusible ligand of the Jak/STAT pathway, Unpaired (Upd), which was recently identified as a downstream target of Notch. However, Notch activity has not been shown to be cell-autonomously required for Upd expression and therefore yet another diffusible signal may be required for Notch activation of Upd. Our results clarify the Notch requirement, demonstrating that Notch activity at the DV-midline leads to cell-autonomous expression of Upd as monitored in loss and gain-of-function Notch clones. In addition, mutations in the Jak/STAT pathway interact genetically with the Notch pathway by suppressing Notch mediated overgrowth. N(act) clones show non-autonomous effects on the cell cycle anterior to the furrow, indicating function of the Jak/STAT pathway. However, cell-autonomous effects of Notch within and posterior to the furrow are independent of Upd. Here, Notch autonomously maintains cells in a proliferative state and blocks photoreceptor differentiation.