肿瘤问题ppt课件

ZYY制作 顾 健 人 上海市肿瘤研究所 癌基因及相关基因国家重点实验室 1 ZYY制作 1. 现有“生物信息学”的限制： “有眼不识泰山” 第一外显子 识别能力 外显子内含子 识别能力 2. 一个基因：不同剪切体 Splicing form (Isoform) 3. 一个基因 蛋白质 切割： 蛋白质 1 肽段 人基因组计划已经给了我们多少？ 人人基因有多少个？基因有多少个？ 10万 3万？ 2 ZYY制作 4. 同一个蛋白质 细胞内的不同 “定位” 不同功能！ 5. 98 DNA序列：功能不明 ! （95） 细胞核细胞质 线粒体 细胞膜 蛋白质移位 Translocation 3 ZYY制作 E1b E1 Exon 2 Exon 3 p16 Ink 4a P14 ARF (human) P19 ARF (mouse) Cross Talk Cross Talk betwerenbetweren OncogenesOncogenes PKC 4E-BP dissociation & release of elf-4E cap dependent initiation translation of 5-UTR P P P P 36 ZYY制作 P1 (3) K dependent cyelin D3 Phosphorylation of Rb and p107 E2F Involved in P1 (3) K and Akt tumorigenesis Dependent on Phosphorylation & activation of p70S6K Ribosomal S6 Ribosomal S6 KinaseKinase S6K1, S6K2 S6K1, S6K2 Regulator of cell growth & protein translation p70S6K short isoform of S6K 1 Cytoplasic in large part Activation is blocked by rapamycin Mediate mTOR effect on protein-translation Phosphorylation of S6 subunit (40s rs protein) S6 translation of 5 ter. Pyr-rich tract (5-TOP mRNA) Also involved in cell cycleAlso involved in cell cycle 37 ZYY制作 WntWnt Pathway Pathway Wnt Wnt 1 = ( int-1, mouse MMTV integration activated gene) Porcupine: A gene for wnt secretion Polytopic membrane protein Related to acyl transferase Frizzled ( Fz ) Wnt Receptor Dally: Co-receptor of Wnt Glypican-type heparan sulfate proteoglycan Glycosyl-Ptd Ins moiety membrane b-catenin: in absence of Wnt Destabilized by a protein complex Dishevelled (Dsh) activated by Wnt-Fz binding Axin APC GSK-3b (Glycogen synthase kinase) GSK - 3b - b-catenin - b catenin degradation Wnt Fz binding Dsh GSK - 3b b-catenin stabilized enter nucleus Nuclear transcription factor: Tcf / LEF: activated by b-catenin P P P P 38 ZYY制作 WntWnt Pathway Pathway Dsh APC GSK 3b b-catenin Axin TCF / LEF APC GSK 3b Dsh Axin TCF / LEF b-catenin b-catenin Wnt LRPFz 39 ZYY制作 Hedgehog Hedgehog PothwayPothway Hedgehog: Embryonic development inducer Hh, hh: Humna Shh (Sonic hh) Ihh (Indian hh) Dhh (Desert hh) 19KD protein C Cholesterol ester N Palmitoylation (after cholesterol addition, enhancing signaling) Secretion of hh: 2 genes: Dispatched related to hh R Patched hh release Toutvelu: enzyme, heparin-SO4 synthesis for transport and response of hh Receceptor of hh Patched (Ptc): Ts, 12 Span-transmembrane Proton-driven lipid transportor Smoothened (Smo): Onc, 7-transmembrane p ( Fz like ) 40 ZYY制作 1. hh (-): ( in a complex) hh (+): 2. Smo activated: coupled with a complex 3. hh (-): (1) Ci N ter. transcription repressor (Ci 75) (2) Ci in cytoplasm ( Cos2 / Fu / Su / Ci complex anchored on microtubule) 4. hh (+): Costa / Fu / Su / Ci dissociated from microtubule Ci (Full length): enters nucleus Transcription of genes ( ptc, Hip and growth genes) Activation of Activation of hhhh Pathway Pathway Ptc Smo hh Ptc Smo* hh - PtcSmo* Smo* FuFu CosCos 2 2 SuSuCiCi Fu: Fused, S / T PK Su: Suppressor of Fu Costa 2 ( Cos. 2 ) : Kinase like Ci: Cubitus interuptus, ZF TA Gli in mammal PKA 41 ZYY制作 Su Fused (Fu) Costa 2 PKAPKA Smoothened (Smo) Patched (Prc) Hedgehog (Hedgehog (HhHh) ) C i C iGrowth gene product Ptc Hip PatehedPatehed: : DisrfunctinDisrfuncti