细胞信号通路Cellular_Apoptosis_Pathway
Wnt信号通路途径调控细胞凋亡在肿瘤治疗中的作用
Wnt信号通路途径调控细胞凋亡在肿瘤治疗中的作用Wnt信号通路在生物体内参与调节了很多生命过程，其中包括各个组织的形成及器官的产生、免疫作用的发生、机体应激性的产生、细胞癌变和细胞凋亡与抗凋亡的过程等重要生命活动。
越来越多的研究揭示了Wnt信号通路在细胞凋亡过程中的巨大作用，当然，Wnt信号通路通过很多已知的途径进行细胞凋亡过程的调节，其中包括通过调整细胞所处的外环境从而刺激细胞凋亡过程的加速或减缓等过程。
本文将在Wnt细胞信号通路调控细胞凋亡从影响肿瘤细胞生长及生物体发育上对近期发表的研究成果作簡要综述，并对Wnt信号通路中存在的关键基因、转录蛋白质做重点介绍并对其在细胞凋亡过程中所起的重要作用加以详细阐述。
[Abstract] Wnt signaling transduction pathway plays an important role in many kinds of life activities,such as the formation of various organizations and organs,immunity,reflex activity,canceration of the normal cell and anti-apoptotic process.The association between the Wnt signaling pathway and apoptosis has become more firmly established in the recent scientific literature.The activity of Wnt signaling according to specific cellular environment stimuli can regulate apoptosis.In this review,we will summarize the recent researches about the apoptosis transferred by Wnt signaling transduction pathway which interfere the activity of cancer cell and the development of organism,and we will also draw attention to genes and proteins of the Wnt signaling pathway involved in apoptosis and describe some of their functional effects.[Key words] Wnt signaling pathway;Apoptosis;Cancer therapy各项研究充分表明，如果细胞凋亡发生失调，那么机体会出现多种疾病，当细胞凋亡不能正常进行时，会发生癌症；当细胞凋亡失调，特别是神经组织或肌肉组织发生病变时，会发生神经或肌肉细胞的功能丧失，导致功能性失常和障碍[1]。
细胞生物学名词解释 (2)
名词解释：1.cellular aging：即细胞衰老，是指细胞在执行生命活动的过程中，随着时间的推移，细胞的增殖能力和生理功能逐渐出现衰退的过程。
2.cell biology：即细胞生物学，是研究细胞生命现象发生的规律及其本质的科学。
3.cell differentiation：即细胞分化，是指由同一来源的细胞（如受精卵）逐渐产生出形态结构、功能和生化特征各不相同的一类细胞群，形成这种稳定性差异的过程称为细胞分化。
4.gene differential expression：即基因差异性表达，多细胞生物个体发育与细胞分化过程中，其基因组DNA 并不全部表达，而呈现选择性表达，它们按照一定的时空顺序，在不同性别和同一细胞的不同发育阶段发生差异性表达。
5.Cysteine aspartic acid speific protease：即半胱氨酸天冬氨酸特异性蛋白酶，简写为Caspase，是一类半胱氨酸蛋白水解酶，为线虫凋亡基因ced-3的同源物，是引起细胞凋亡的关键酶。
6.Caspase：是一类半胱氨酸蛋白水解酶，简称为Caspase；为线虫凋亡基因ced-3的同源物，是引起细胞凋亡的关键酶。
7.Apoptosis：即细胞凋亡，是指细胞在一定的生理或病理条件下，一种主动的由基因决定的细胞自杀过程。
8.限制点（restriction point）：或者称为启动点是G0期细胞进入G1早期的一个检查点，也是哺乳动物细胞周期G1晚期控制进入S期的调节点，相当于酵母的Start检查点。
9.检查点（checkpoint）：是细胞周期中的一套保证DNA复制和染色体分配质量的检查机制。
10.收缩环（contractile ring）：紧贴于细胞分裂部位细胞膜内侧，包含可收缩的肌动蛋白束和肌球蛋白II。
一．简述细胞衰老的意义及研究途径。
细胞衰老研究具有越来越重要的意义：细胞衰老是机体衰老和死亡的基础，也是众多老年性疾病的基础。
细胞信号通路大全
1PPAR信号通路：过氧化物酶体增殖物激活受体(PPARs)是与维甲酸、类固醇和甲状腺激素受体相关的配体激活转录因子超家族核激素受体成员。
它们作为脂肪传感器调节脂肪代谢酶的转录。
PPARs由PPARα、PPARβ和PPARγ3种亚型组成。
PPARα主要在脂肪酸代谢水平高的组织，如：肝、棕色脂肪、心、肾和骨骼肌表达。
他通过调控靶基因的表达而调节机体许多生理功能包括能量代谢、生长发育等。
另外，他还通过调节脂质代谢的生物感受器而调节细胞生长、分化与凋亡。
PPARa同时也是一种磷酸化蛋白，他受多种磷酸化酶的调节包括丝裂原激活蛋白激酶(ERK-和p38．MAPK)，蛋白激酶A和C(PKA，PKC)，AMPK和糖原合成酶一3(GSK3)等调控。
调控PPARa生长信号的酶报道有MAPK、PKA和GSK3。
PPARβ广泛表达于各种组织，而PPARγ主要局限表达在血和棕色脂肪，其他组织如骨骼肌和心肌有少量表达。
PPAR-γ在诸如炎症、动脉粥样硬化、胰岛素抵抗和糖代谢调节，以及肿瘤和肥胖等方面均有着举足轻重的作用，而其众多生物学效应则是通过启动或参与的复杂信号通路予以实现。
鉴于目前人们对PPAR—γ信号通路尚不甚清，PPARs通常是通过与9-cis维甲酸受体(RXR)结合实现其转录活性的。
2MAPK信号通路:mapk简介:丝裂原激活蛋白激酶（mitogen—activatedproteinkinase，MAPK）是广泛存在于动植物细胞中的一类丝氨酸/苏氨酸蛋白激酶。
作用主要是将细胞外刺激信号转导至细胞及其核内，并引起细胞的生物化学反应（增殖、分化、凋亡、应激等）。
MAPKs家族的亚族:ERKs（extracellularsignalregulatedkinase) ：包括ERK1、ERK2。
生长因子、细胞因子或激素激活此通路，介导细胞增殖、分化。
JNKs(c-JunN-terminalkinase)包括JNK1、JNK2、JNK3。
APOPTOSIS.ppt
activated either by autocatalyic cleavage or by other proteases: cascade of casepases 4. Total 14 members (11 in human), and caspase-2, 3, 6, 7, 8, 9, and 10 are known to be involved in apoptosis
Pro-caspases Bcl-xL Bcl-2 BID
MEKK-1 PKC and PAK2/hPAK65 p21WAF1/CIP1 FAK
Transcription factors/regulators MDM2
RB Sp1 IkB-a
DNA/RNA damage and repair mechanisms
PARP与DNA修复、基因完整性监护有关
Important Substrates of Caspases
Structural/trafficking proteins Actin
Fodrin Gelsolin Nuclear lamins A, B, C
Regulatory/signaling proteins
Discovery of Bcl-2
p53 discovered as an apoptosis regulator
Role Cytochrome c and apoptosome confirmed
1887
1965 1972 19771982 1987 1989 1991 1993 1996-7 2000
参与细胞信号转导通路的蛋白简写及全拼
参与细胞信号转导通路的蛋白简写及全拼4E-BP eIF4E binding proteinAbl Ableson protein tyrosine kinaseACTR A histone acetyltransferaseAIF Programmed cell death protein 8ANT Adenine nucleotide translocation channelApaf-1 Apoptotic protease activating factor 1APP beta-Amyloid precursor proteinAPPs Acute phase proteinsASIP Agouti switch proteinASK Apoptosis signal-regulating kinase (e.g., ASK1)ATF-2 Activating transcription factor 2ATM Ataxia telangiectasia¿mutated protein kinaseATR ATM and Rad3¿related protein kinaseBam32 B-cell adaptor molecule 32 kDaBCAP B-cell adaptor for PI3KBcl-10 B-cell leukemia 10 proteinBfl-1 Bcl-2-related protein A1Bid A BH3 domain¿only death agonist proteinBimp1 B-lymphocyte-induced maturation protein 1BLNK B-cell linker proteinBRCA Breast cancer growth suppressor proteinBtk BrutonÍs tyrosine kinaseC3G Guanine nucleotide¿releasing factor 2CAD Caspase-activated deoxyribonucleaseCam CalmodulinCaMK Calcium/calmodulin-dependent kinaseCAP c-Cbl-associated proteinCas p130CAS, Crk-associated substrateCaspase Cysteine proteases with aspartate specificityCBL Cellular homologue of the v-Cbl oncogeneCBP CREB binding proteinCD19 B-lymphocyte antigen CD19CD22 B-cell receptor CD22CD40 B-cell surface antigen CD40CD45 Leukocyte common antigen, a phospho-tyrosine phosphataseCD5 Lymphocyte antigen CD5cdc2 Cell division cycle protein 2, CDK1cdc34 Cell division cycle protein 34, a ubiquitin conjugating (E2) enzyme cdc42 Cell division cycle protein 42, a G-proteinCDK Cyclin-dependent kinaseChk Checkpoint kinaseCHOP C/EBP homologous protein 10Cip CDK-interacting proteinCIS Cytokine inducible SH2-containing proteinc-Myb Cellular homologue of avian myeloblastosis virus oncogenec-Myc Cellular homologue of avian myelocytomatosis virus oncogeneCREB cAMP response element¿binding proteinCRK Proto-oncogene c-CrkCrkII One of three cellular homologues of the v-Crk oncogeneDAG DiacylglycerolDaxx Fas death domain¿associated proteinDiablo Direct IAP binding protein with low pIDNA-PK DNA-activated protein kinaseDP1 Member of the E2F transcription factor familyDPC4 Deleted in pancreatic cancer locus 4 (also Smad4)DR3 Death receptor 3dsRNA Double-stranded RNAE2F Transcription factor family including E2F- and DP-like subunitseEF Eukaryotic elongation factorEgr-1 Early growth response protein 1eIF Eukaryotic initiation factorElk-1 Ets domain proteinENaC Epithelial sodium channelEPAC Exchange protein activated by cAMPER Endoplasmic reticulumER Estrogen receptorErk Extracellular signal-regulated kinaseETS C-ets-1 protein, a transcription factorFADD Fas-associated protein with death domainFAK Focal adhesion kinaseRII Immunoglobulin gamma Fc region receptor II-B FcFKHR Forkhead in rhabdomyosarcomaFLIP FLICE (Caspase-8) inhibitory proteinFRAP FKBP12-rapamycin-associated proteinFRS2 Lipid anchored Grb2 binding protein activated by FGF receptorFyn A Src family proto-oncogene tyrosine-protein kinaseGab1 GRB2-associated binder-1GADD34 Growth arrest and DNA damage protein 34GADD45 Growth arrest and DNA damage protein 45GAP GTPase activating proteinsGAS IFNgamma-activated sequencesGas2 Growth arrest¿specific gene 2GCK Germinal center kinaseGCN2 General control of amino acid biosynthesis protein 2, an S/T kinaseGCN5 General control of amino acid biosynthesis protein 5, a histone acetyltransferase GEF Guanine nucleotide exchange factorGLUT-4 Glucose transporter type 4GPCR G-protein coupled receptorGRB2 Growth factor receptor¿bound protein 2GRB10 Growth factor receptor¿bound protein 10GRIP Glucocorticoid receptor interacting protein, a histone acetyltransferase GRK G-protein coupled receptor kinaseGlycogen synthase kinase-3 betaβGSK-3HDAC Histone deacetylaseHMG High mobility groupHPK Hematopoietic progenitor kinaseHRI Hemin-regulated inhibitorHrk/DP5 Harakiri protein, an activator of apoptosisHSP27 Heat shock protein 27IAP Inhibitor of apoptosisICAD Inhibitor of caspase-activated deoxyribonucleaseB Inhibitor of NF-kappa BκIIKK I-kappa-B kinaseINK4 Inhibitor of CDK4IRS Insulin receptor substrate (e.g., IRS-1)ISRE Interferon-stimulated response elementJak Janus-family tyrosine kinaseJIP-1 JNK interacting protein 1。
细胞凋亡的信号途径
细胞凋亡的意义 ：
细胞凋亡普遍存在于生物界，既发生于生理状态下， 也发生于病理状态下。
细胞凋亡对胚胎发育及形态发生（morphogenesis）、 组织内正常细胞群的稳定、机体的防御和免疫反应、 疾病或中毒时引起的细胞损伤、老化、肿瘤的发生进 展起着重要作用，并具有潜在的治疗意义，至今仍是 生物医学研究的热点。
Extrinsic (receptor mediated)
Intrinsic (mitochondrial homeostasis)
Damage (p53)
Bax,Bak
(effector)
Caspase 9 (initiator)
干预凋亡Fas信号传导：
Fas 受体途径
*Fas在肝病如肝损伤、肝炎、肝硬化和肝癌等的发病机制上起 到一个重要的调节作用；*Fas信号通路还可促进神经再生。
Fas 受体途径
1. Fas Death-signaling pathway
DD DED
DD DED
FLIP
X
FLIP
Casp 8
caspases 3, 6, 7 Apoptosis
caspases 3, 6, 7 Apoptosis
FADD -------FADD(Fas-associated protein with death domain C端的死亡结构域(DD)和N端死亡效应结构域(DED),DD结构域与Fas及TNF受体家族中的其它受体中的DD结构域结合,接受凋亡信号.
Extrinsic apoptotic pathway
凋亡的受体途径
Death receptor-induced signaling
2003 0276
Hale Waihona Puke Cell-extrinsic and cell-intrinsic apoptotic signaling pathways
细胞信号通路大全
信号通路与免疫系统疾病
自身免疫疾病
自身免疫疾病患者体内免疫细胞信号通路异 常激活，如T细胞、B细胞等信号通路，导致 自身免疫反应过度。
炎症性疾病
炎症性疾病患者体内炎症细胞信号通路异常激活， 如NF-κB、MAPK等信号通路，导致炎症反应过度 或持续。
感染性疾病
感染性疾病患者体内病原微生物通过干扰免 疫细胞信号通路，如细菌、病毒等，逃避免 疫细胞的攻击。
PI3K-Akt信号通路
PI3K-Akt信号通路是细胞生存和增殖的关键信号转导途径。
PI3K-Akt信号通路在细胞生长、代谢、存活和凋亡等过程中发挥重要作用。当细胞受到生长因子、激素等刺激时，PI3K被激 活，进而催化生成PIP3，后者与Akt结合并使其磷酸化，从而激活Akt。Akt可以进一步调控下游的靶蛋白，参与细胞增殖、 迁移、代谢等过程。
JAK-STAT信号通路
JAK-STAT信号通路是细胞因子信号转导的重要途径之一。
JAK-STAT信号通路在细胞因子信号转导中发挥关键作用。当细胞因子与受体结合后，JAK被激活并催 化受体酪氨酸磷酸化，进而招募并磷酸化STAT蛋白。STAT蛋白形成二聚体并进入细胞核，调控靶基 因的表达，参与细胞生长、分化、免疫调节等过程。
信号通路的自调节
信号通路的正反馈调节
自调节的一种形式是正反馈调节，它通过增 加某个关键信号分子的数量或活性，进一步 增强自身的信号传递。例如，某些生长因子 可以诱导自身受体的表达，形成一个正反馈 环路，不断放大信号传递。
信号通路的负反馈调节
另一种自调节形式是负反馈调节，它通过降 低某个关键信号分子的数量或活性，来抑制 自身的信号传递。例如，某些激素可以通过 诱导产生拮抗性激素或受体，从而抑制自身 的信号传递。
细胞凋亡及信号通路详解(收藏)
内质网主导的细胞凋亡1.细胞凋亡的概念2.细胞凋亡的分类2.1细胞凋亡的内部线粒体途径2.2细胞凋亡的内部内质网途径2.3细胞凋亡的外部死亡受体途径1.细胞凋亡的概念细胞凋亡是指机体在生理或病理条件下，为了维持自身内环境的稳态，通过基因调控使细胞产生主动、有序的死亡；同时伴随着一系列形态和生化方面的变化，包括核固缩、DNA片段化、细胞膜重塑和起泡、细胞皱缩、形成凋亡小体等，最后凋亡的细胞被巨噬细胞吞噬而消亡。
细胞凋亡是细胞为了更好地适应其内外环境而引发的死亡过程，它是一种正常的细胞死亡，涉及一系列基因的激活、表达及调控等。
在细胞凋亡整个过程中，质膜保持完整，细胞无内容物外溢，不引起炎症反应。
2.细胞凋亡的分类凋亡发生的途径分为内源性线粒体途径、内源性内质网途径、外源性死亡受体途径；或者某些条件下的granzyme B介导的凋亡过程。
2.1 细胞凋亡的内部线粒体途径细胞凋亡的内部线粒体途径：当细胞受到内部凋亡刺激因子作用，如癌基因的活化DNA损伤、细胞缺氧、细胞生长因子缺失等，可激活细胞内部线粒体凋亡途径，引起细胞凋亡；内部线粒体凋亡途径也可以被死亡配体所激活。
在该途径中，Bcl-2家族蛋白通过调节膜电位从而控制线粒体外膜通透性。
2.1.1Bcl-2家族Bcl-2家族蛋白是控制线粒体相关的凋亡因子释放的主要调节因子。
根据它们在细胞凋亡中的作用可分为两类：促凋亡蛋白和抗凋亡蛋白，其中促凋亡蛋白还可以分为具有BH1-3结构域的蛋白和只具有BH3结构域的蛋白。
促凋亡蛋白成员中的Bak以及抗凋亡蛋白成员如Bcl-2，Bcl-xL等主要存在于线粒体膜上；其他成员如Bid、Bad主要存在于胞质中。
Bax一般存在于胞质中，当接收到凋亡信号时，Bax重新定位于线粒体表面，在线粒体表面构成跨线粒体膜的孔，导致膜电位降低，膜通透性增加，从而释放凋亡因子。
目前关于Bax、Bak的激活方式，存在两种假说：直接激活模式和间接激活模式。
细胞信号通路大全
1 PPAR信号通路：过氧化物酶体增殖物激活受体( PPARs) 是与维甲酸、类固醇和甲状腺激素受体相关的配体激活转录因子超家族核激素受体成员。
它们作为脂肪传感器调节脂肪代谢酶的转录。
PPARs由PPARα、PPARβ和PPARγ 3种亚型组成。
PPARα主要在脂肪酸代谢水平高的组织，如：肝、棕色脂肪、心、肾和骨骼肌表达。
他通过调控靶基因的表达而调节机体许多生理功能包括能量代谢、生长发育等。
另外，他还通过调节脂质代谢的生物感受器而调节细胞生长、分化与凋亡。
PPARa同时也是一种磷酸化蛋白，他受多种磷酸化酶的调节包括丝裂原激活蛋白激酶( ERK-和p38．M APK) ，蛋白激酶A和C( PKA，PKC) ，AM PK和糖原合成酶一3( G SK3) 等调控。
调控PPARa生长信号的酶报道有M APK、PKA和G SK3。
PPARβ广泛表达于各种组织，而PPAR γ主要局限表达在血和棕色脂肪，其他组织如骨骼肌和心肌有少量表达。
PPAR-γ在诸如炎症、动脉粥样硬化、胰岛素抵抗和糖代谢调节，以及肿瘤和肥胖等方面均有着举足轻重的作用，而其众多生物学效应则是通过启动或参与的复杂信号通路予以实现。
鉴于目前人们对PPAR—γ信号通路尚不甚清，PPARs 通常是通过与9-cis维甲酸受体( RXR)结合实现其转录活性的。
2 MAPK信号通路:mapk简介:丝裂原激活蛋白激酶（mitogen—activated protein kinase，MAPK）是广泛存在于动植物细胞中的一类丝氨酸/苏氨酸蛋白激酶。
作用主要是将细胞外刺激信号转导至细胞及其核内，并引起细胞的生物化学反应（增殖、分化、凋亡、应激等）。
MAPKs家族的亚族 :ERKs（extracellular signal regulated kinase)：包括ERK1、ERK2。
生长因子、细胞因子或激素激活此通路，介导细胞增殖、分化。
JNKs(c-Jun N-terminal kinase)包括JNK1、JNK2、JNK3。
CSE1L与恶性肿瘤的临床研究进展
CSE1L与恶性肿瘤的临床研究进展摘要】CSE1L，又称为细胞凋亡易感基因，定位在人染色体20q13，与酵母染色体分离基因(CSE 1)同源，高表达于多种癌组织类型中。
本文着重探讨CSE1L的生物学功能及其在恶性肿瘤中的研究进展，并展望其研究前景。
【关键词】CSE1L；恶性肿瘤；生物标志物；MHS6【中图分类号】R730 【文献标识码】A 【文章编号】2095-1752（2018）11-0007-02CSE1L（染色体分离样蛋1），又称为细胞凋亡易感基因(cellular apoptosis susceptibility，CAS)，最早发现于乳腺癌细胞，定位于人染色体20q13上，与酵母染色体分离基因(CSE 1)同源，高表达于肝癌、前列腺癌、乳腺癌和胃癌细胞中。
其表达产物CSE1L作为核转运因子，参与调节细胞凋亡[1]、增殖[2]、染色体聚集[3]、微泡形成[4,5]及癌转移[2]，并在早期胚胎生长发育过程中发挥重要作用[6]。
另外，CSE1L也是一项癌症血清生物标志物。
研究表明，CSE1L可以调节RAS诱导下的ERK（细胞外调节蛋白激酶），还可以调节CREB（环磷腺苷效应元件结合蛋白）和MITF（小眼畸形相关转录因子）的过表达和磷酸化过程，并由此参与黑色素原形成和黑色素瘤进展[7]，而ERK信号通路是大部分癌症靶向药物的重要作用靶点。
因此，CSE1L可作为一项潜在的血清标志物，用来监控靶向治疗中的药物耐药性。
1.CSE1L分子生物学功能CSE1L蛋白分子量约100kDa，共由971个氨基酸组成，表达于细胞浆中。
其分子生物学功能为介导转入蛋白(Importin α)从胞核到胞浆的回收[8]。
1.1 Importin α从胞浆到胞核的过程位于胞质中的转运蛋白(NLS)先与Importin α结合，再与Importin β结合形成NLS—Importin α/β复合体，NPC内核孔素蛋白与上诉复合体上的Importin β位点结合，并将该复合体定位在NPC胞质纤丝上，然后将复合体递呈到细胞NPC中央插销蛋白上，再通过解离、结合和平衡作用，复合体被送入细胞核内。
细胞凋亡详解-附过程示意图
细胞凋亡细胞凋亡（apoptosis）指为维持内环境稳定，由基因控制的细胞自主的有序的死亡。
细胞凋亡与细胞坏死不同，细胞凋亡不是一件被动的过程，而是主动过程，它涉及一系列基因的激活、表达以及调控等的作用，它并不是病理条件下，自体损伤的一种现象，而是为更好地适应生存环境而主动争取的一种死亡过程。
中文名细胞凋亡外文名ApoptosisApoptosis 美[ˌæpɔpˈtoʊsɪz] n.程序性细胞死亡，细胞凋落，细胞凋亡a type of cell death in which the cell uses specialized cellular machinery to kill itself人体内的细胞注定是要死亡的，有些死亡是生理性的，有些死亡则是病理性的，有关细胞死亡过程的研究，已成为生物学、医学研究的一个热点。
人们已经知道细胞的死亡起码有两种方式，即细胞坏死与细胞凋亡（apoptosis）。
细胞坏死是早已被认识到的一种细胞死亡方式，而细胞凋亡则是逐渐被认识的一种细胞死亡方式。
细胞凋亡是细胞的一种基本生物学现象，在多细胞生物去除不需要的或异常的细胞中起着必要的作用。
它在生物体的进化、内环境的稳定以及多个系统的发育中起着重要的作用。
细胞凋亡不仅是一种特殊的细胞死亡类型，而且具有重要的生物学意义及复杂的分子生物学机制。
凋亡是多基因严格控制的过程。
这些基因在种属之间非常保守，如Bcl-2家族、caspase家族、癌基因如C-myc、抑癌基因P53等，随着分子生物学技术的发展对多种细胞凋亡的过程有了相当的认识，但是迄今为止凋亡过程确切机制尚不完全清楚。
而凋亡过程的紊乱可能与许多疾病的发生有直接或间接的关系。
如肿瘤、自身免疫性疾病等，能够诱发细胞凋亡的因素很多，如射线、药物等。
人的部分生理结构属于自然凋亡，如人的有尾阶段，尾部在发育过程中自动凋亡。
研究历史1．凋亡概念的形成1965年澳大利亚科学家发现，结扎鼠门静脉后，电镜观察到肝实质组织中有一些散在的死亡细胞，这些细胞的溶酶体并未被破坏，显然不同于细胞坏死。
p53信号通路
p53 SignalingRT² Profiler™ PCR Arrayp53 Signaling Pathway PCR ArrayCellular Senescence PCR ArrayDNA Damage Signaling Pathway PCR ArrayCell Cycle PCR ArraySureSilencing RNAip53 Signaling Pathway Gene RNAiCellular Senescence Gene RNAiDNA Damage Signaling Pathway Gene RNAiCell Cycle Gene RNAiCignal™ Reporter Assaysp53 Pathway Reporter Assay KitE2F Reporter Assay KitEGR1 Reporter Kitp53 is a tumour suppressor protein that regulates the expression of a wide variety of genes involved in Apoptosis, Growth arrest, Inhibition of cell cycle progression, Differentiation and accelerated DNA repair or Senescence in response to Genotoxic or Cellular Stress. As a transcription factor, p53 is compos ed of an N-terminal Activation Domain, a central specific DNA Binding Domain, and a C-terminal Tetramerization Domain, followed by a Regulatory Domain rich in basic Amino acids. Having a short half-life, p53 is normally maintained at low levels in unstress ed mammalian cells by continuous ubiquitylation and subsequentdegradation by the 26S Proteasome. Nonphosphorylated p53 is ubiquitylated by the MDM2 (Mouse Double Minute-2) ubiquitin ligase. MDM2 binding inactivates p53 by two mechanisms. First, MDM2 binds to the transactivation domain of p53, precluding interaction with the transcriptional machinery. Second, this binding mediates the covalent attachment of ubiquitin to p53. Ubiquitylated p53 is then degraded by the Proteasome. Thus MDM2 acts as a major reg ulator of the tumor suppressor p53 by targeting its destruction. When the cell is confronted with stress like DNA damage, Hypoxia, Cytokines, Metabolic changes, Vi ral infection, or Oncogenes, however, p53 ubiquitylation is suppressed and p53 accumulates in the nucleus, where it is activated and stabilized by undergoing multiple covalent modifications including Phosphorylation and Acetylation (Ref.1 & 2).Phosphorylation of p53 mostly occurs in the N-terminal activation domain at the Ser6, Ser9, Ser15, Thr18, Ser20, Ser33, Ser37, Ser46, Thr55, and Thr81 residues, with some phosphorylation occurring in the C-terminal linker and basic regions at Ser315, Ser371, Ser376, Ser378, and Ser392. Phosphorylation on most of these sites is induced by DNA damage, with som e, such as Thr55 and Ser376, being repressed upon genotoxic stress. p53 phosphorylation is mediated by several cellular kinases including Chks (Checkpoint Kinases), CSNK1-Delta (Casein Kinase-1-Delta), CSNK2 (Casein Kinase-2), PKA (Protein Kinase A), CDK7 (Cyclin-Dependent Kinase-7), DNA-PK (DNA-Activated- Protein Kinase), HIPK2 (Homeodomain-Interacting Protein Kinase-2), CAK (CDK-Activating Kinase), p38 and JNK (Jun NH2-terminal kinase). Notably, phosphorylation at Ser15 by ATM (Ataxia Telangiectasia Mutated Gene)/ATR (Ataxia-Telangiectasia and Rad3 Related), either directly or through Chk1 (Cell Cycle Checkpoint Kinase-1)/Chk2 (Cell Cycle Checkpoint Kinase-2), or at Ser20 by Chk1/Chk2 has been shown to alleviate the inhibition or degradation of p53, leading to p53 stabilization and activation. The phosphorylation-induced p53 stabilization and activation are mediated through multiple mechanisms and may vary according to the cellular context or microenvironment. HIF-1Alpha (Hypoxia-Inducible Factor-1-Alpha) has been implicated to be involved in p53 stabilization, the precise mechanism by which HIF-1Alpha regulates p53-mediated function remains unknown. Recently, the interaction between p53 and HIF-1Alpha was reported to evoke HIF-1Alpha degradation. Members of the PIAS (Protein Inhibitor of Activated STAT) protein family have also been found to interact with p53. PIAS1 and PIAS-Gamma function as SUMO (Small Ubiquitin Related Modifier-1) ligases for p53. Moreover, the RING finger domain of PIAS1 binds to the C-terminus of the tumor suppressor p53 and catalyzes its sumoylation, a modification which represses p53 activity on a reporter plasmid containing consensus p53 DNA binding sites. PML (Promyelocytic Leukemia) also activates p53 by recruiting it to multiprotein complexes termed PML-nuclear bodies. PML is a tumor suppressor protein and the major component of multiprotein nuclear complexes that have been variably termed Kremer bodies, ND10, PODs (for PML Oncogenic Domains), and PML-NBs (PML-Nuclear Bodies). PML binds directly with p53 and recruits it to PML-NBs. Recruitment to PML-NBs activate p53 by bringing it in close proximity with CBP (CREB-Binding Protein) /p300. BRCA1 (Breast Cancer-1 Gene) and p53 can also physically associate, both in vitro and in vivo and function in a common pathway of tumor suppression. The ability of BRCA1 to biochemically modulate p53 function suggests that this may be afundamental role of BRCA1 in tumor suppression (Ref.3, 4 & 5).Another important modification of p53 is acetylation. p53 is specifically acetylated at Lys370, Lys372, Lys373, Lys381, and Lys382 by p300/CBP and at Lys320 by PCAF (p300/CBP-associated factor). Acetylation has been shown to augment p53 DNA binding, and to stimulate p53-mediated transactivation of its downstream target genes through the recruitment of coactivators. Acetylation may also regulate the stability of p53 by inhibiting its ubiquitination by MDM2. In vivo, acetylation at Lys320, Lys373, and Lys382 is induced by many genotoxic agents, including UV-radiation, IR (Ionizing Radiation), hypoxia, oxidative stress, and even depletion of ribonucleotide pools. p53 can also be deacetylated by HDAC1 (Histone Deacetylase-1) and SIRT1. Human SIRT1 is an enzyme that deacetylates the p53 tumor suppressor protein and has been suggested to modulate p53-dependent functions including DNA damage-induced cell death. p53 deacetylation has been suggested to down-regulate the activation of genes such as Bax and p21WAF1. Phosphorylation and acetylation are interdependent. In deed, phosphorylation at the p53N-terminus has been shown to enhance its interaction with acetylase p300/CBP and to potentiate p53 acetylation. Activated p53 functions effectively as a transcription factor and induces transcription of several genes. The D NA targets of p53 are consensussequences consisting of a 10-base pair repeat of 5'-PuPuPu-C(A/T)(T/A)GPyPyPy-3' (where Pu is a purine and Py is a pyrimidine). It also can bind to a palindromic site having a four or five-base pair inverted repeat of a similar sequence. Complete p53 is inactive for specific DNA binding unless activated by covalent and noncovalent modifications of the basic C-terminal domain. After p53 is activated it can be involved in cell-cycle inhibition, apoptosis, genetic repair, and inhibition of blood-vesselformation (Ref.5, 6 & 7).Cell cycle inhibition takes place when there is a block in cell-cycle division. p53 does this by stimulating the expression of p21 WAF1/CIP1 (Cyclin Dependent Kinase Inhibitor-p21). This protein is an inhibitor of CDKs (Cyclin-Dependent Kinases) that regulate the cell cycle via perturbation of their partner cyclin. Cyclins are involved to ensure successful transitions from S phase to G1. Since p21 WAF1/CIP1 inhibits CDKs it results in inhibition of both G1-to-S and G2-to-mitosis transitions by causing hypophosphorylation of Rb (Retinoblastoma) and preventing the release of E2F. Additionally p53 can stimulate 14-3-3, a protein that sequesters Cyclin B1-CDK1 complexes out of the nucleus. This results in a G2 block. Activated p53 may also initiate apoptosis and stop cell proliferation. p53 stimulates a wide network of signals that act through two major apoptotic pathways: Extrinsic Pathways and Intrinsic Pathways. The extrinsic pathway involves engagement of pa rticular `death' receptors that belong to the TNFR (Tumor Necrosis Factor Receptor) family and, through the formation of the DISC(Death-Inducing-Signaling-Complex), leads to a cascade of activation of Caspases, including Caspase8 and Caspase3, which in turn induce apoptosis. Most common death receptors involved in extrinsic apoptosis Fas, DR5 (Death Receptor-5) and PERP. The intrinsic apoptotic pathway is dominated by the Bcl2 (B-Cell CLL/Lymphoma-2) family of proteins, which governs the release of CytoC (Cytochrome-C) from the mitochondria. The Bcl2 family comprises anti-apoptotic (pro-survival) and pro-apoptotic members. The Bcl2 family is divisible into three classes: pro-survival proteins, whose members are most structurally similar to Bcl2, such as BclXL; pro-apoptotic proteins, BAX (Bcl2 Associated-X Protein) and BAK (Bcl2 Antagonist Killer-1), which are structurally similar to Bcl2 and BclXL and antagonize their pro-survival functions; and the pro-apoptotic `BH3-only' proteins. Intriguingly, a key subset of the Bcl2 family genes are p53 targets, including BAX, Noxa, PUMA (p53-Upregulated Modulator of Apoptosis) and the most recently identified, BID (BH3 Interacting Domain Death Agonist). p53 may also inhibit Bcl2 that is an inhibitor of apoptosis. p53 may also have a role in maintaining genetic stability by 'nucleotide-excision' repair of DNA, chromosomal recombination and chromosome segmentation. GADD45 (Growth Arrest- and DNA Damage-Inducible Gene-45) is a multifunctional protein that is regulated by p53 and that may play a role in DNA repair and cell cycle checkpoints. p53 can playa role in the inhibition of blood-vessel formation. In order for tumours to reach a large size, they must initiate the growth of nutrient-bringing blood vessels in their vicinity, the process of angiogenesis. p53 stimulates the production of genes that prevent this process from happening. p53 activates the expression of the Tsp1 (Thrombospondin-1), an anti-angiogenic factor, along with other angiogenesis inhibitor BAI1 (Brain-specific Angiogenesis Inhibitor-1) (Ref. 8, 9 & 10).In addition, p53 regulates MDM2 function in a negative feedback loop, because the MDM2 gene is a target for p53. Therefore, activation of p53 eventually leads to its own inactivation by switching on a pathway that leads to its destruction. MDM2 is subject to further regulation by direct binding of the ARF (Active Response Factor) protein, which prevents MDM2-mediated p53 proteolysis. PTEN (Phosphatase and Tensin Homolog), on the other hand inhibits MDM2-mediated p53 degradation. p53 can transcriptionally activate PTEN, which may further inhibit Akt activity. Therefore, inhibition of Akt by the inhibitors may trigger a positive feedback with perhaps additional anti-tumor effects. The c-Fos proto-oncogene is also a target for transactivation by the p53 tumor suppressor. Mutations in p53 are associated with genomic instability and increased susceptibility to cancer. It is the most frequently mutated protein in all cancer with an estimated 60% of all cancers having mutated forms that affect its growth suppressing activities. However some common tumours have a higher incidence such that 90% of cervical and 70% of colorectal are found to have p53 mutations. The p53 protein can be inactivated in several ways, in cluding inherited mutations that result in a higher incidence of certain familial cancers such as Li-Fraumeni syndrome. Certain DNA tumour viruses, such as the human adenovirus and the papilomavirus, bind to and inactivate the protein. Functional p53 is th ought to provide a protective effectagainst tumorigenesis (Ref.2, 11 & 12).。
细胞凋亡的线粒体途径
Mitochondrial Pathways in physiological cell death
If mitochondria are pivotal in controlling cell life and death, then how do these organelles kill? At least three general mechanisms are known, and their effects may be interrelated, including (i) disruption of electron transport, oxidative phosphorylation, and adenosine triphosphate (ATP) production; (ii) release of proteins that trigger activation of caspase family proteases; and (iii) alteration of cellular reduction-oxidation (redox) potential
disruptionofelectrontransportandenergymetabolism线粒体跨膜电位的耗散与细胞凋亡有密切关系近年来陆续有报道说明线粒体跨膜电位的耗散早于核酸酶的激活也早于磷酯酰丝氨酸暴露于细胞表面
细胞凋亡的线粒体途径
蒋舜媛 董霞 程在全
2002-12-17
细胞死亡损伤性死亡 Nhomakorabea生化特征:
染色质降解, 核小体间连接DNA部位被降解,产 生寡聚核小体DNA片段,即180-200DP 整数倍 的不同长度的DNA片断.
Fig.1. Schematic summary of biochemical mechanisms of apoptosis.
细胞信号通路大全
1 PPAR信号通路：过氧化物酶体增殖物激活受体( PPARs) 是与维甲酸、类固醇和甲状腺激素受体相关的配体激活转录因子超家族核激素受体成员。
它们作为脂肪传感器调节脂肪代谢酶的转录。
PPARs由PPARα、PPARβ和PPARγ 3种亚型组成。
PPARα主要在脂肪酸代谢水平高的组织，如：肝、棕色脂肪、心、肾和骨骼肌表达.他通过调控靶基因的表达而调节机体许多生理功能包括能量代谢、生长发育等.另外，他还通过调节脂质代谢的生物感受器而调节细胞生长、分化与凋亡。
PPARa同时也是一种磷酸化蛋白,他受多种磷酸化酶的调节包括丝裂原激活蛋白激酶( ERK—和p38．M APK) ，蛋白激酶A和C（ PKA，PKC） ,AM PK和糖原合成酶一3（ G SK3）等调控.调控PPARa生长信号的酶报道有M APK、PKA和G SK3.PPARβ广泛表达于各种组织，而PPAR γ主要局限表达在血和棕色脂肪，其他组织如骨骼肌和心肌有少量表达。
PPAR—γ在诸如炎症、动脉粥样硬化、胰岛素抵抗和糖代谢调节，以及肿瘤和肥胖等方面均有着举足轻重的作用，而其众多生物学效应则是通过启动或参与的复杂信号通路予以实现。
鉴于目前人们对PPAR—γ信号通路尚不甚清,PPARs通常是通过与9—cis维甲酸受体( RXR）结合实现其转录活性的.2 MAPK信号通路：mapk简介:丝裂原激活蛋白激酶（mitogen—activated protein kinase，MAPK）是广泛存在于动植物细胞中的一类丝氨酸/苏氨酸蛋白激酶。
作用主要是将细胞外刺激信号转导至细胞及其核内，并引起细胞的生物化学反应（增殖、分化、凋亡、应激等).MAPKs家族的亚族 :ERKs(extracellular signal regulated kinase）：包括ERK1、ERK2。
生长因子、细胞因子或激素激活此通路,介导细胞增殖、分化. JNKs(c—Jun N-terminal kinase)包括JNK1、JNK2、JNK3。
运动对线粒体介导骨骼肌细胞凋亡信号通路的影响
中国细胞生物学学报Chinese JoumalofCell Biology 2021,43(1): 118-124 DOI: 10.11844/cjcb.2021.01.0015运动对线粒体介导骨骼肌细胞凋亡信号通路的影响蔺海旗1陈亮2王震3林文鼓元宇(1华南理工大学体育学院，广州510641;2广州中医药大学体育健康学院，广州510006;3广东青年职业学院，广州510545;4广州体育学院运动与健康学院，广州510500)摘要 细胞凋亡是一种程序化的细跑死亡方式，其信号传导通路分为外源性和内源性两条 主要途径，线粒体在内源性细胞凋亡途径中扮演着重要的角色。
研究表明，运动可通过调节线粒体 介导骨骼肌细胞凋亡的进程，而运动调节线粒体介导骨骼肌细胞凋亡信号通路影响机体细胞生物 进程的机制仍有待研究。
该文主要阐述了线粒体介导细胞凋亡信号传导通路及运动对其的调控作 用机制，旨在为线粒体相关代谢性疾病的防治提供运动干预理论基础。
关键词运动；线粒体;骨骼肌;细胞凋亡;肌肉衰减症Effects of Exercise on the Signaling Pathway of Mitochondrial-MediatedSkeletal Muscle’s ApoptosisL I N Haiqi',C H E N Liang2,W A N G Z h e n3,L I N W e n t a o4*,Y U A N Y u4*(^College o f P hysical Education, South China University o f Technology, Guangzhou 510641, China;2I nstitute o f P hysical Education and Health, Guangzhou University o f Chinese Medicine, Guangzhou 510006, China; lGuang Dong Youth Vocational College, Guangzhou 510545, China, 4School o f S ports and Health, Guangzhou Sport University, Guangzhou 510500, China)Abstract Apoptosis is a p r o g r a m m e d cell death.Its signal transduction pathway can be divided into exogenous and endogenous pathways.Mitochondria plays an important role in the intrinsic apoptotic pathway.I t has been found that exercise can regulate the process of mitochondrial mediated apoptosis of skeletal muscle cells.H o w e v e r,the m e c h a n i s m of motor regulation of mitochondria-mediated skeletal muscle cell apoptosis signaling pathway affecting the cellular biological processes has not been clarified.This article mainly elaborates the signal transduction pathway of mitochondria-mediated apoptosis and the m e c h a n i s m of exercise regulating the signal transduction pathway,aiming to provide a theoretical basis for exercise intervention for the prevention and treatment of mitochondrial-related metabolic diseases.K e y w o r d s exercise;mitochondria;skeletal muscle;cell apoptosis;sarcopenia细胞凋亡是指机体为维持内环境稳定，由基因 明，运动应激使线粒体膜通透性改变并释放凋亡因调控的细胞自主程序性死亡方式吒其中线粒体在 子，进而激活细胞凋亡信号通路，诱导细胞凋亡[|3]。
细胞信号传导途径中的磷脂酰肌醇信号机制研究
细胞信号传导途径中的磷脂酰肌醇信号机制研究磷脂酰肌醇（phosphatidylinositol，PI）信号通路是细胞内信号传导的一个重要途径。
PI信号通路运用磷脂酰肌醇作为信号分子，通过对于磷酸化作用的调控转化为可调节的次信号分子以起调节细胞功能的作用。
磷脂酰肌醇信号传导途径是细胞最重要的调节方式之一，通过完善相关分子与机制的研究可以为生物医学研究、分子药理学研究等带来重大改善。
因此，对磷脂酰肌醇信号传导途径的研究，对于探究细胞应激、细胞生长、正常发育以及疾病的发生等都具有重大的意义。
磷脂酰肌醇信号通路在细胞信号传导中发挥着重要的作用。
其起始物为磷酸脂酰肌醇(ip)2，经过磷酸化作用并分解成为磷酸脂酰肌醇(ip)3和diacylglycerol(DAG). 这两种次信号分子分别作用于荧光素C催化酶和蛋白激酶C( protein kians C, PKC)所依赖的酶，从而调节细胞内钙（Ca2+）的浓度并控制PKC途径的激活。
磷酸酯酶(to hydrolyze the 5'-phosphate from PIP) 不能有效地降解磷酸脂酰肌醇二酰胺(PIP2) 以及-2-磷酸脂酰肌醇(IP2), 大量存在的IP3 通过双向作用，向内向平面，使钙从内质网释放，从而积累到胞内以起到下游信号分子CAMP（ cyclic adenosine monophosphate, cAMP)的激活作用；而DAG则直接刺激PKC途径。
DAG为PKC的激活剂，而且PKC亚型的表观特异性主要源自于不同的激活剂/DAG的识别。
在研究过程中，自上世纪80年代的发现磷脂酰肌醇信号途径以来，种类繁多的信号作用路劲相关蛋白和其他成分的发现以及作用特性的研究为后来更加深入的研究奠定基础。
例如，与当时相比大量的氨基酸残基序列已经被鉴定为含有磷酸肽，其作用是启动并转导细胞信号的一般机制。
而磷酸肽通常依赖于一类万能的磷酸化酶，称作蛋白磷酸酶，该酶具有除去磷酸肽中的磷酸基团的能力，功能主要是修饰蛋白丝，重组蛋白和酶。
医学细胞生物学ip3途径
医学细胞生物学ip3途径
细胞生物学是研究细胞结构、功能和生理活动的学科，而IP3途径则是细胞内信号传导的重要机制之一。
IP3（inositol trisphosphate）是一种重要的细胞内信号分子，它在细胞内钙离子的释放和信号传导中起着关键作用。
在细胞内，IP3的产生通常是由G蛋白偶联受体（G protein-coupled receptor）或酪氨酸激酶受体的激活引起的。
当这些受体受到外界信号刺激时，它们会激活磷脂酶C（phospholipase C），导致磷脂酰肌醇双酯（PIP2）分解成IP3和二酰甘油（DAG）。
IP3随后会与内质网膜上的IP3受体结合，引发内质网钙离子通道的开放，释放细胞内钙离子。
这些钙离子可以触发细胞内多种生物化学反应，例如激活钙调蛋白激酶、调节基因转录等，从而影响细胞的生理功能。
在医学上，IP3途径在许多生理和病理过程中都扮演着重要角色。
例如，它参与调节心肌细胞的收缩和舒张，影响血管平滑肌细胞的收缩，调节胰岛素的分泌以及在神经元中传递信号等。
此外，IP3途径的异常也与一些疾病如癌症、神经退行性疾病和心血管疾病等有关。
总的来说，IP3途径在细胞生物学和医学中具有重要意义，它对细胞内钙离子的调节和信号传导起着关键作用，对于我们理解细胞功能和疾病发生发展具有重要意义。
希望这个回答能够从多个角度全面地解答你的问题。