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1、翟中和 王喜忠 丁明孝 主编 细胞生物学（第细胞生物学（第4版）版）Copyright 高等教育出版社 2011 Regulation of cell proliferation and cancer cells 细胞增殖调控与癌细胞细胞增殖调控与癌细胞Chapter 14Fangdong Zou, Sichuan UniversitySection 1 Regulation of Cell Proliferation 1. Cell-cycle control system and CheckpointsCell-cycle control system safely guides the
2、cell through the events of the cell cycleIn 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翟中和 王喜忠 丁明孝 主编 细胞生物学
3、（第4版） 高等教育出版社 2011 Maturation-promoting factor / Mitosis-promoting factor 2. MPF: transition from G2 to MM phase HeLa cell with a rat kangaroo PtK2 cell, 1974, Humangenetik (引自翟中和等，2011)Does the cytoplasm of cells contain regulatory factors that affect cell cycle activities? (1) Discovery Amphibian
4、oocytes and early embryos of frogs(引自翟中和等，2011)(引自翟中和等，2011)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 cycleInterphaseIn
5、terphaseMitosisMitosisMitosisMPF activityHighLow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 Tim Hunt found cyclin in 1983: sea urchin eggsWhen 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
6、 divide in two. This was a stunning, startling discovery.“35S-Met: Fertilized eggs16 min60 min 85 min 120 minSamples after fertilized Cyclin: in sea urchin eggs that is destroyed at each cleavage division. Cell, 1983, 33:389-396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 In the mid-1970s as a postdoc stu
7、dying the fission yeast S. pombe. Divide before they had reached full size: Mutants wee: Wee1，wee2The 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） cdc2D Normal cdc2-Cdc2 encodes a protein kin
8、ase with 34kD whose activity is required for cells to enter M phase.(p34cdc2)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 Hartwell found cdc28What is the relationship between cyclins or cdc2 and MPF?MPF purification: 1988 (Xenopus egg)MPF=32kD+45kDMPF has protein kinase activityCdc2Cyclin BCdc2cyclin-depe
9、ndent kinase (Cdk)cyclinM phase Cyclin-Cdk (MPF)(Cyclin-dependent protein kinase)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 MPF的发现的发现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，p34cdc2，Cdc28海胆卵细胞：Cyclin的发现MPF生化成分：Cdc2 和 Cyclinthe 2001 Nobel Prize for Physiology or Medicine翟中和 王喜忠 丁明孝 主编 细胞生物学（第
10、4版） 高等教育出版社 2011 (2) Activation of MPF By cyclinmitosismitosisinterphaseinterphaseCyclin concentrationBy phosphatase and KinaseMolecular Biology of the Cell ( Garland Science 2008)Cell and Molecular Biology ( John Wiley & Sons 2010)Active MPF activate MPF again 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
11、 (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, ERAll of these processes are thought to be triggered when M-Cdk phosphorylates specific proteins
12、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 一位教授在实验室分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
13、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？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 3. APC: metaphaseanaphase transitionThe APC triggers sister-chromatid seperation and the completion of mitosisAPC (anaphase-promoting complex, or cyclosome): ubiquitin
14、 ligase family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 Spindle assembly checkpointInactive APC Cdc20Active APC SecruinInactive separaseUbiquitin systemActive separase CohesinG2MetaphaseAnaphaseM-CdkUnattached chromosomes block sister-chromatid seperationThe inaproriately attached kinetochores somehow
15、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-APCM-cyclin inactivion: control of proteolysis by Cdc20-APC. Cell exists from mitosisChildren with Down syndrome. The disease is caused
16、 by trisomy 21, meaning their bodies cells have an extra chromosome 21 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 4. G1 checkpointMechanisms controlling cell-cycle entry and S-phase initiation in animal cellsThe Rb proteins itself was identified originally through studies an inherited eye cancer in chil
17、dren, retinoblastoma.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 5. The diversity of cyclin-Cdk complexG1-cyclins: 促使细胞通过G1checkpointG1/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mitosisCyclin-Cdk Vertebrates Budding Yeast G1 cyclinD Cdk4,6 Cln3 Cdk1 G1/S cyclinE Cdk2 Cln1,2
18、 Cdk1 S cyclinA Cdk2 Clb5,6 Cdk1 M cyclinB Cdk1 Clb1,2,3,4 Cdk1Cdk1: cdc2 in vertebrates and fission yeast, cdc28 in budding yeastVarious cyclin-Cdk complexes are regulated by:(1)在不同时相各种Cyclins的合成与降解(2)Cyclin-Cdk 复合物被不同Kinase和Phosphatase作用翟中和 王喜忠 丁明孝 主编 细胞生物学（第4版） 高等教育出版社 2011 6. Inhibition of cell
19、cycle progression(1)Binding of Cdk inhibitor proteins (CKIs/ CDIs)(2)Turn off cyclin and Cdk gene expression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 DNA damage and p53DNA damage checkpoints: in late G1 or in late G2Inhibiting G1/S and S cyclin-Cdk complexUbiquitin ligaseDasgupta et al., Proc. Natl Aca
20、d. Sci. USA, 2006, 103: 6332-6337 What happens if DNA damage is so severe that repair is not possible?Unicellular organismsMulticellular organismsDNA damage-p53-apoptosisIf the DNA damage cannot repaired, p53 activates the transcription of genes that trigger cell death via apoptosis翟中和 王喜忠 丁明孝 主编 细胞
21、生物学（第4版） 高等教育出版社 2011 p53: Guardian of the genomeCell and Molecular Biology ( John Wiley & Sons 2010)The protein kinases Chk1 and Chk2 also block cell cycle progression by phosphorylation of Cdc25 family.Degradation in a Ubiquitin-proteasome dependent pathwayDNA damageChk1Chk2 ATM/ATRCDC25ACyclinE,
22、A/Cdk2Section 2 Cancer Cellshttp:/ and CancerTumor Benign tumor：Do not spreadMalignant tumor Cancer：Metastasize2000-2003Cell and Molecular Biology ( John Wiley & Sons 2010)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 1. Basic properties of a cancer cell(1)Cell proliferate uncontrollablyDefectivecontrolofc
23、elldeath,celldifferentiation,orDefectivecontrolofcelldeath,celldifferentiation,orbothbothAlteredinresponsetoDNAdAlteredinresponsetoDNAdamageandotherformsamageandotherformsofstressofstressTelomerase:replicativecellsenescenceTelomerase:replicativecellsenescence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 (2
24、) Invade and metastasize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 (3) Less well differentiated than normal cells or benign tumor cells(4) Have highly aberrant chromosome complementsAneuploidy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 (5) Lose Contact inhibition in vitroCell and Molecular Biology ( John Wil
25、ey & Sons 2010)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 2. The causes of cancer Carcinogenic chemicals and UVDNA and RNA tumor viruses SV40, Adenovirus HIVBenign tumorMalignant tumorNormal cellAlter the genome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 (1) Proto-oncogens Gain-of-function mutationsRas oncog
26、ene: Retain bind GTPBcl-2 oncogene: Prevent apoptosisCell and Molecular Biology ( John Wiley & Sons 2010)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 (2) Tumor suppressor genes: Loss-of-function mutationsCell and Molecular Biology ( John Wiley & Sons 2010)Rb gene: The first tumor suppressor gene in patien
27、t with retinoblastomap53: Guardian of the genomeBecause the accumulation of gene mutation and Natural selection, so the patient is agedCancer stem cellsThey may be less sensitive to treatments.Molecular Biology of the Cell ( Garland Science 2008)Hoechst 33342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 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56 个基因突变翟中和 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 Thank you!
