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1、ZYY制作1ZYY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？2ZYY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 Translocation3ZYY制作E1b E1 Exon 2 Exon 3p16 Ink 4a P14 ARF (human) P19 ARF
2、(mouse)Cross Talk Cross Talk betwerenbetweren OncogenesOncogenes PKC 4E-BP dissociation & release of elf-4E cap dependent initiation translation of 5-UTRP PP P36ZYY制作P1 (3) K dependent cyelin D3 Phosphorylation of Rb and p107 E2F Involved in P1 (3) K and Akt tumorigenesis Dependent on Phosphorylatio
3、n & activation of p70S6KRibosomal S6 Ribosomal S6 KinaseKinase S6K1, S6K2S6K1, S6K2Regulator of cell growth & protein translationp70S6K short isoform of S6K 1Cytoplasic in large partActivation is blocked by rapamycinMediate mTOR effect on protein-translationPhosphorylation of S6 subunit (40s rs prot
4、ein)S6 translation of 5 ter. Pyr-rich tract (5-TOP mRNA) Also involved in cell cycleAlso involved in cell cycle37ZYY制作WntWnt PathwayPathway Wnt Wnt 1 = ( int-1, mouse MMTV integration activated gene)Porcupine: A gene for wnt secretion Polytopic membrane proteinRelated to acyl transferaseFrizzled ( F
5、z ) Wnt ReceptorDally: Co-receptor of WntGlypican-type heparan sulfate proteoglycanGlycosyl-Ptd Ins moiety membraneb-catenin: in absence of WntDestabilized by a protein complex Dishevelled (Dsh) activated by Wnt-Fz binding AxinAPCGSK-3b (Glycogen synthase kinase)GSK - 3b - b-catenin - b catenin degr
6、adationWnt Fz binding Dsh GSK - 3bb-catenin stabilizedenter nucleus Nuclear transcription factor: Tcf / LEF: activated by b-cateninP PP P38ZYY制作WntWnt Pathway PathwayDshAPCGSK 3bb-cateninAxinTCF / LEFAPCGSK 3bDshAxinTCF / LEFb-cateninb-cateninWntLRPFz39ZYY制作Hedgehog Hedgehog PothwayPothwayHedgehog:
7、Embryonic development inducerHh, hh: Humna Shh (Sonic hh)Ihh (Indian hh)Dhh (Desert hh)19KD protein C Cholesterol esterN Palmitoylation (after cholesterol addition, enhancing signaling)Secretion of hh: 2 genes: Dispatched related to hh R Patchedhh releaseToutvelu: enzyme, heparin-SO4 synthesis for t
8、ransport and response of hhRececeptor of hhPatched (Ptc): Ts, 12 Span-transmembrane Proton-driven lipid transportorSmoothened (Smo): Onc, 7-transmembrane p ( Fz like )40ZYY制作1. hh (-): ( in a complex)hh (+):2. Smo activated:coupled with a complex3. hh (-): (1) Ci N ter. transcription repressor (Ci 7
9、5)(2) Ci in cytoplasm ( Cos2 / Fu / Su / Ci complex anchored on microtubule)4. hh (+): Costa / Fu / Su / Ci dissociated from microtubuleCi (Full length): enters nucleusTranscription of genes ( ptc, Hip and growth genes)Activation of Activation of hhhh Pathway PathwayPtc Smohh Ptc Smo*hh - PtcSmo*Smo
10、* FuFuCos 2Cos 2 SuSuCiCiFu: Fused, S / T PKSu: Suppressor of FuCosta 2 ( Cos. 2 ) : Kinase likeCi: Cubitus interuptus,ZF TAGli in mammalPKA41ZYY制作SuFused (Fu)Costa 2PKAPKASmoothened (Smo)Patched (Prc)Hedgehog (Hedgehog (HhHh) )C iC iGrowthgene productPtc HipPatehedPatehed: : DisrfunctinDisrfunctin in BCC in BCCSmoSmo: mutated in breast Hedgehog Pathway: mutated in breast Hedgehog PathwayMiT microtubuleMitSu Fused (Fu)Costa 2C i( Ci 75 )Mit42ZYY制作43
