研究生讲座-细胞稳态与-1.ppt

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,*,细,胞,周,期,阻,滞,细,胞,衰,老,细,胞,凋,亡,细,胞,坏,死,细,胞,自,噬,反,应,细胞稳态及其维系机制,肿瘤,、,神经退行性疾病,、,心血管病,、,II,糖尿病等,STOP,细胞稳态维系机制,细胞稳态,DNA,损伤修复,应答反应,DNA,损伤,/,基因组不稳定的内在因素,DNA,损伤修复,应答反应途径,p53,p-ATM,53BP1,H2AX,p-Chk2,Oncogene,activation,Tumor suppressor,inactivation,Telomeres,shortening,Oxidative,Stress,细胞衰老,细胞凋亡,细胞周期阻滞,DNA,损伤,与细胞稳态维系,细胞稳态维系机制,细胞自噬,细胞坏死,DNA,损伤,/,基因组不稳定的内在因素,抑癌基因异常,原癌基因激活,自由基滞留,端粒缩短,p53,p-ATM,p-CHK2,53BP1,H2AX,衰老组织,53BP1,-H2AX,癌前病变,肿瘤,癌前病变,/,肿瘤组织,正常衰老组织细胞,DNA,损伤修复,反应,与细胞衰老及肿瘤的发生发展,老化细胞,p-ATM,p-Chk2,Cao Liu,et al.,Cancer gets the Chkered flag.Nat Med.12:1 354-6,2006.,BRCA-1,NBS1,FANCD2,BLM,RAD51,DMC1,ATM,NBS1,BLM,FANCD2,Ataxia Telangiectasia Mutated,Nijmegen Breakage Syndrome,Bloom Syndrome,Fanconi Anemia,肿瘤抑制基因,(BRCA1),功能缺陷对,肿瘤与衰老形成的影响,DNA,损伤修复,细胞稳态,Brca1-/-,Wt,细胞凋亡检测,细胞增殖检测,抑癌基因功能异常与细胞稳态,胚胎鼠,WT,Brca1,-/-,细胞衰老检测,Xu X,Qiao W,Cao Liu,et,al.,Nat Genet.28(3):266-71,2001,.,抑癌基因功能异常与,DNA,损伤修复应答,p53,Actin,Chk2,Wt,p21,BRCA1,-/-,Wt,Cao Liu,*,et al.Mol Cell.35(4):534-41,2009.,磷酸化,DNA,甲基化,DNA,甲基化,(,染色体端粒,-,原位杂交,),Wt,BRCA1,BRCA1,-/-,-,半乳糖苷酶染色,(SA-gal),p53,p21,Actin,Wt,BRCA1,-/-,1 5,1 5,1 5,BRCA1,-/-,p53,-/-,WT,BRCA1,-/-,DNA,损伤修复应答与细胞周期阻滞及衰老,Cao,Liu,et al.Genes&Development.17(2):201-13,2003.,细胞衰老,(%),细胞传代,DNA,损伤修复应答与,肿瘤形成及早衰,生存率,(%),BRCA1,-/-,Chk2,-/-,BRCA1,-/-,Atm,-/-,BRCA1,-/-,p53,-/-,WT,WT,0 10 20 30 40 50,周数,生存率,(%),p53,+/-,BRCA1,-/-,p53,+/-,BRCA1,-/-,p53,+/-,BRCA1,-/-,p53,-/-,Cao,Liu,et al.,EMBO J,.25(10):2167-77,2006.,Mol Cell,.,2009.,Brca1,-/-,53BP1,-/-,Brca1,-/-,Tumore free(%),DNA,damage,Chk2,p53,p-(Thr68),p-(Ser-20),53BP1,DNA,损伤修复反应,DNA,损伤修复应答与,肿瘤形成及早衰,Rad51,Brca1,-/-,53BP1,-/-,WT,Brca1,-/-,Brca1,-/-,53BP1,-/-,0%,11%,1%,WT,Brca1,-/-,Rad51,NHEJ,53BP1,X,Brca1,-/-,53BP1,+/+,HR,X,Brca1,Cell,.2010.,HR,NHEJ,Brca1,-/-,53BP1,-/-,53BP1,Brca1,HR,NHEJ,Brca1,53BP1,Brca1,+/+,53BP1,+/+,HR,NHEJ,Rad51,Rad51,DNA,损伤修复的稳态,Liu,H,Fergusson,MM,Castiho,RM,Liu,J,Cao,Liu,Chen,J,Malide,G,Rovira,II Schimel,D,Kuo,CJ,Gutkind,JS,Hwang,PM and Finkel T.,Science,.,10;317(5839)803-806,2007.,Control,Wnt,Wnt,Control,HP1-,a,g,-H2AX,53BP1,p-ATM,原癌基因激活,DNA,损伤反应,、,诱导细胞衰老,WT,Bmi1,-/-,53BP1,表达,WT,Bmi1,-/-,线粒体功能低下引发,DNA,损伤应答,自由基表达,NAC,(,ROS,抑制,),Chk2,磷酸化,Actin,癌基因,BMI-1,与细胞能量代谢稳态,Liu J,Cao Liu,*,et,al.,Nature,.459(7245):387-92,2009.,DNA,损伤修复应答反应,与,衰老,细胞自噬的发生机制,Atg,(,autophagy related gene,),自噬前体,自噬体,V-ATPase,溶酶体,细胞核,自噬,溶酶体,线粒体,ATP,细胞自噬,细胞能量代谢稳态调控,V-ATPase,自噬体,溶酶体,自噬前体,线粒体,细胞自噬与细胞周期调控的协同作用,细胞稳态,“,开源,”,Atg7,?,“,节流,”,ATP,代谢应激,细胞自噬,自噬相关基因,Atg7,调控,p53,功能,IP(myc-Atg7),+-+,WB(Flag-p53),Starvation,(min),0 30 60,IP:p53,WB:Atg7,Starvation,(hr):,0 0.5 1 3,p21,Atg7,Actin,0 0.5 1 3,Atg7-/-,Atg7+/+,-H2AX,WT,Atg7,-/-,ROS,Chk2,p53,Apoptosi,p-(Thr68),p-(Ser-20),Atg7-/-,Atg7+/+,Starvation,(hrs):,0,1,3,5,p-(Thr68)Chk2,Atg7,Actin,0,1,3,5,Starvation,(hrs):,p-(Ser-20)p53,p53,Actin,Chk2+/+,0 3,0 3,Chk2-/-,自噬异常与,DNA,损伤反应,Atg7,Metabolic Stress,V-ATPase,ATP,OPEN,ATP sources,Autophagosome,Lysosome,Autophagolysome,ACT cycle,Autophagy,Science,.,21012.,细胞稳态,G1,S,G2,M,p53,p21,Cell Cycle,Cell cycle,arrest,Cutting,ATP consumption,Checkpoint,细胞自噬与细胞周期调控的协同作用,自噬与衰老及肿瘤形成,Cell Rep,.,2013.,Cell Rep,.,2013.,自噬与衰老及肿瘤形成,Cell Rep,.,2013.,Old,Old,mTOR+/+,mTOR+/+,mTOR+/+,mTOR+/+,mTOR-/-,mTOR-/-,young,自噬与衰老及肿瘤形成,Cell Rep,.,2013.,自噬与衰老及肿瘤形成,TNF-a,信号对细胞稳态维系的调控,RIP1,RIP3,?,Sirt2,去乙酰化修饰调控,RIP1-RIP3,复合体形成,TNF:,-,+,-,+,IP,:IgG IRP1 IRP1 IgG IRP1 IRP1,WB:IRP3,WB:IRP1,TNF:,-,+,IP:,IgG Sirt2 Sirt2,WB:IRP3,WB:Sirt2,TNF:,-,+,-,+,Sirt2+,/,+,Sirt2-,/,-,IP:,AcK AcK AcK AcK,WB:HA-IRP1,WB:HA-IRP1,WB:actin,Sirt2+,/,+,Sirt2-,/,-,WB:HA-IRP1,WB:HA-IRP1,WB:actin,TNF:,-,+,-,+,IP:,AcK AcK AcK AcK,Sirt2,抑制剂,：,-+,抑制,Sirt2,活性防止缺血性心肌梗死,动物水平,心肌梗死面积,Sirt2,去乙酰化修饰调控程序性细胞坏死,Nisha N,Borensten R,Sun J,Wong R,Fergusson M,Lee IH,Liu J,Rovira I,Cheng HL,Lombard D,Alt F,Sack M,Murphy E,Cao Liu,Finkel T.,Nature,.,492(7428):199-204,2012.,蛋白修饰,抑制剂干预,Sirt2,Sirt2,RIP3,RIP3,RIP1,RIP1,Ac,Ac,TNF,a,RIP3,RIP3,RIP1,RIP1,Ac,Ac,TNF,a,STOP,Necrosis,Necrosis,细胞稳态维系机制的,“,双刃剑,”,效应,健康,细胞凋亡,细胞衰老,疾病,阴阳平衡,细胞坏死,细胞自噬,细胞周期阻滞,