第四版 _细胞增殖调控与癌细胞(英文)

,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,翟中和 王喜忠 丁明孝 主编 细胞生物学（第,4,版）,高等教育出版社,2011,翟中和 王喜忠 丁明孝 主编,细胞生物学（第,4,版）,Copyright ,高等教育出版社,2011,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,翟中和 王喜忠 丁明孝 主编,细胞生物学（第,4,版）,Copyright ,高等教育出版社,2011,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,Regulation of cell proliferation and cancer cells,细胞增殖调控与癌细胞,Chapter 14,Fangdong Zou, Sichuan University,Section 1 Regulation of Cell Proliferation,1. Cell-cycle control system and Checkpoints,Cell-cycle control system safely guides the cell through the events of the cell cycle,In most eucaryotic cells, the cell-cycle control system triggers cell-cycle progression at three major regulatory transitions, or checkpoints,(From the World of the Cell, 2000),Cell-cycle control system: cyclically activated protein kinases,Maturation-promoting factor,/ Mitosis-promoting factor,2,.,MPF: transition from G,2,to M,M phase HeLa cell with a rat kangaroo PtK2 cell, 1974, Humangenetik,(引自翟中和等，2021),Does the cytoplasm of cells contain regulatory factors that affect cell cycle activities?,(1) Discovery,Amphibian oocytes and early embryos of frogs,(引自翟中和等，2021),(引自翟中和等，2021),Masui and Markerts experiments (J. Exp. Zool. 1971, 177: 142),Whats the role of hormone?,Trigger protein synthesis,1978, MPF activity undergoes dramatic fluctuations in cleaving eggs that correlate with changes in the cell cycle,Interphase,Interphase,Mitosis,Mitosis,Mitosis,MPF activity,High,Low,Tim Hunt found,cyclin,in,1983: sea urchin eggs,When the gel was developed on Friday 23 July 1982, I found that the strongest band early on suddenly got very much weaker at about the time when the eggs were about to divide in two. This was a stunning, startling discovery.“,35,S-Met: Fertilized eggs,16 min,60 min,85 min,120 min,Samples after fertilized,Cyclin: in sea urchin eggs that is destroyed at each cleavage division.,Cell, 1983, 33:389-396,In the mid-1970s,as a postdoc studying the fission yeast,S. pombe,.,Divide before they had reached full size: Mutants ,wee:,Wee1,，,wee2,The,wee2,gene was later renamed,cell division cycle 2,(,CDC2,is,identical in function to,CDC28,from,budding yeast,1982,).,Nurse found,cdc2,University of Oxford,cdc,2,D,Normal,cdc,2,-,Cdc2 encodes a protein kinase with 34kD whose activity is required for cells to enter M phase.(p34,cdc2,),Hartwell found,cdc28,What is the relationship between cyclins or cdc2 and MPF?,MPF purification: 1988 (,Xenopus,egg),MPF=32kD+45kD,MPF has protein kinase activity,Cdc2,Cyclin B,Cdc2,cyclin-dependent kinase (Cdk),cyclin,M phase Cyclin-Cdk (MPF),(Cyclin-dependent protein kinase),MPF,的发现,HeLa,细胞融合：,有丝分裂促进因子,非洲爪蟾卵细胞提取物注射：,MPF,概念提出,酵母温度敏感突变株：,cdc,基因，,p34,cdc2,，,Cdc28,海胆卵细胞：,Cyclin,的发现,MPF,生化成分：,Cdc2,和,Cyclin,the 2001 Nobel Prize for Physiology or Medicine,(2) Activation of MPF,By cyclin,mitosis,mitosis,interphase,interphase,Cyclin concentration,By phosphatase and Kinase,Molecular Biology of the Cell ( Garland Science 2021),Cell and Molecular Biology ( John Wiley & Sons 2021),Active MPF activate MPF again,(3) Functions of MPF: G2 M transition,M-Cdk,induce the assembly of the mitotic spindle,trigger chromosome condensation,?,nuclear envelope breakdown,?,cytoskeleton rearrangement,reorganization of Golgi, ER,All of these processes are thought to be triggered when M-Cdk phosphorylates specific proteins,M-Cdk does not act along. The Polo-like kinase and the Aurora kinase also make important contributions to the control of early mitotic events.,Activation of Polo-like kinases and Aurora kinases depends on M-Cdk,一位教授在实验室别离得到两株突变酵母，cdc25-和wee1-, 但忘了标记这两株酵母分别是什么突变。根据细胞周期调控的相关知识，你只需用一台光学显微镜观察野生型、突变型酵母的增殖形态，便可轻易给这位教授解决这个难题。,野生型 突变株,1,突变株,2,(1),突变株,1,和突变株,2,分别是什么突变？ 为什么？,(2),两株突变酵母的哪一周期时相发生了改变？这一时相是变,长还是变短？,3. APC: metaphaseanaphase transition,The APC triggers sister-chromatid seperation and the completion of mitosis,APC (anaphase-promoting complex, or cyclosome): ubiquitin ligase family,Spindle assembly checkpoint,Inactive APC,Cdc20,Active APC,Secruin,Inactive separase,Ubiquitin system,Active separase,Cohesin,G2,Metaphase,Anaphase,M-Cdk,Unattached chromosomes block sister-chromatid seperation,The inaproriately attached kinetochores somehow generate a diffusible signal that bind Cdc20 (APC/C activator).,Mad2 proteins on unattached kinetochores, JCB 1998,(mammalian cell, staining with anti-Mad2),Mad2-cdc20-APC,M-cyclin inactivion: control of proteolysis by Cdc20-APC. Cell exists from mitosis,Children with Down syndrome. The disease is caused by trisomy 21, meaning their bodies cells have an extra chromosome 21,4. G1 checkpoint,Mechanisms controlling cell-cycle entry and S-phase initiation in animal cells,The Rb proteins itself was identified originally through studies an inherited eye cancer in children,retinoblastoma,.,5. The diversity of cyclin-Cdk complex,G1-cyclins:,促使细胞通过,G1checkpoint,G1/S-cyclins:,在,G1,末结合,Cdks,促使细胞,DNA,复制,S-cyclins:,结合,S-Cdk,启动,DNA,复制,M-cyclins:,促使细胞进入,mitosis,Cyclin-Cdk Vertebrates Budding Yeast,G1 cyclinD Cdk4,6 Cln3 Cdk1,G1/S cyclinE Cdk2 Cln1,2 Cdk1,S cyclinA Cdk2 Clb5,6 Cdk1,M cyclinB Cdk1 Clb1,2,3,4 Cdk1,Cdk1: cdc2 in vertebrates and fission yeast,cdc28 in budding yeast,Various cyclin-Cdk complexes are regulated by:,在不同时相各种,Cyclins,的合成与降解,Cyclin-Cdk,复合物被不同,Kinase,和,Phosphatase,作用,6. Inhibition of cell cycle progression,Binding of Cdk inhibitor proteins (CKIs/ CDIs),Turn off cyclin and Cdk gene expression,DNA damage and p53,DNA damage checkpoints:,in late G1 or in late G2,Inhibiting G1/S and S cyclin-Cdk complex,Ubiquitin ligase,Dasgupta et al., Proc. Natl Acad. Sci. USA, 2006, 103: 6332-6337,What happens if DNA damage is so severe that repair is not possible?,Unicellular organisms,Multicellular organisms,DNA damage-p53-apoptosis,If the DNA damage cannot repaired, p53 activates the transcription of genes that trigger cell death via apoptosis,p53: Guardian of the genome,Cell and Molecular Biology ( John Wiley & Sons 2021),The protein kinases Chk1 and Chk2 also block cell cycle progression by phosphorylation of Cdc25 family.,Degradation in a Ubiquitin-proteasome dependent pathway,DNA damage,Chk1,Chk2,ATM/ATR,CDC25A,CyclinE, A/Cdk2,Section 2 Cancer Cells,Tumor and Cancer,Tumor,Benign tumor,：,Do not spread,Malignant tumor Cancer,：,Metastasize,2000-2003,Cell and Molecular Biology ( John Wiley & Sons 2021),1. Basic properties of a cancer cell,(1)Cell proliferate uncontrollably,Defective control of cell death, cell differentiation, or both,Altered in response to DNA d,amage and other forms of stress,Telomerase: replicative cell senescence,(2) Invade and metastasize,(3) Less well differentiated than normal cells or benign tumor cells,(4) Have highly aberrant chromosome complementsAneuploidy,(5) Lose Contact inhibition,in vitro,Cell and Molecular Biology ( John Wiley & Sons 2021),2. The causes of cancer,Carcinogenic chemicals and UV,DNA and RNA tumor viruses,SV40, Adenovirus,HIV,Benign tumor,Malignant tumor,Normal cell,Alter the genome,(1) Proto-oncogens,Gain-of-function mutations,Ras,oncogene:,Retain bind GTP,Bcl,-2 oncogene:,Prevent apoptosis,Cell and Molecular Biology ( John Wiley & Sons 2021),(2) Tumor suppressor genes:,Loss-of-function mutations,Cell and Molecular Biology ( John Wiley & Sons 2021),Rb,gene,: The first tumor suppressor gene in patient with retinoblastoma,p53: Guardian of the genome,Because the accumulation of gene mutation and Natural selection, so the patient is aged,Cancer stem cells,They may be less sensitive to treatments.,Molecular Biology of the Cell ( Garland Science 2021),Hoechst 33342,3. Cancer: As a result of the accumulation of mutation and natural selection,癌症的发生一般并不是单一基因的突变，而至少在一个细胞中发生,5,6,个基因突变,Thank you!,