病理生理学：第11章 细胞增殖和凋亡异常与疾病（英）

1、细胞增殖细胞增殖 细胞分化细胞分化 Apoptosis 凋亡凋亡 Autophagy 自噬自噬 Pyroptosis 细胞焦亡细胞焦亡 Pyronecrosis “焦榈酚坏死焦榈酚坏死” Necrosis 坏死坏死 Oncosis 细胞肿胀死亡（胀亡）细胞肿胀死亡（胀亡） 细胞死亡细胞死亡 Apoptosis 凋亡凋亡 Autophagy 自噬自噬 Pyroptosis 细胞焦亡细胞焦亡 Pyronecrosis “焦榈酚坏死焦榈酚坏死” Necrosis 坏死坏死 Oncosis 细胞肿胀死亡（胀亡）细胞肿胀死亡（胀亡） 细胞死亡细胞死亡 Programmed necrosis （ （nec

2、roptosis) Apoptosis 凋亡凋亡 Autophagy 自噬自噬 Pyroptosis 细胞焦亡细胞焦亡 Pyronecrosis “焦榈酚坏死焦榈酚坏死” Necrosis 坏死坏死 Oncosis 细胞肿胀死亡（胀亡）细胞肿胀死亡（胀亡） 细胞死亡细胞死亡细胞增殖与疾病细胞增殖与疾病细胞凋亡与疾病细胞凋亡与疾病细胞分化与疾病细胞分化与疾病细胞增殖与疾病细胞增殖与疾病细胞凋亡与疾病细胞凋亡与疾病细胞分化与疾病细胞分化与疾病InterphaseCell division Gap 1 (G1) phase (postmitotic/presynthesis gap phase) （

3、 （DNA合成前期）合成前期）From the end of the previous M phase until the beginning of DNA synthesis.This phase is marked by synthesis of various enzymes that are required in S phase, mainly those needed for DNA replication. S phase (DNA synthesis phase) （DNA合成期）合成期）S phase starts when DNA synthesis commences;

4、when it is complete, all of the chromosomes have been replicated, i.e., each chromosome （ （染色体染色体） ）has two (sister) chromatids （ （染色单体）染色单体）. Thus, the amount of DNA in the cell has effectively doubled. Gap 2 (G2) phase (postsynthesis/premitotic gap phase) （DNA合成后期）合成后期）Significant biosynthesis occ

5、urs during this phase, mainly involving the production of microtubules, which are required during the process of mitosis（有丝分裂）（有丝分裂）. Mitotic (M) phase （有丝分裂期）（有丝分裂期） Mitosis and cytokinesis （胞质分裂）（胞质分裂）occur in this phase. The division of the mother cell into two daughter cells.Further divided into

6、 several subphases:Prophase（早期）（早期）, Prometaphase（早中期）（早中期）, Metaphase（中期）（中期）, Anaphase（后期）（后期）, Telophase（末期）（末期）, and Cytokinesis（胞（胞质质分裂期）分裂期）. G0 phase （休眠期）Cells that are not actively dividing may be temporarily removed from the cycle by entering a resting state defined as G0 Phase.Cell cycle

7、control systemCyclins and Cyclin-Dependent Kinases (CDK) 周期蛋白周期蛋白和和周期素依周期素依赖赖性蛋白激性蛋白激酶酶Cell cycle control systemCyclins and Cyclin-Dependent Kinases (CDK) 周期蛋白周期蛋白和和周期素依赖性蛋白激酶周期素依赖性蛋白激酶Cyclins are a family of proteins that control the cell cycle by activating CDK. CyclinN-terminal domain C-terminal

8、domain Cyclin structure:Cell cycle control systemCDK are a family of protein kinases first discovered for their role in regulating the cell cycle. The discovery of the cyclins and CDK was awarded 2001 Nobel Prize in Physiology or Medicine. Cyclins and Cyclin-Dependent Kinases (CDK) 周期蛋白周期蛋白和和周期素依赖性蛋

9、白激酶周期素依赖性蛋白激酶Cyclins(15 families29 members)Cyclin ACyclin BCyclin CCyclin DCyclin ECyclin FCyclin GCyclin HCyclin ICyclin JCyclin KCyclin LCyclin OCyclin TCyclin YCDKs(13 CDKs)CDK 1CDK 2CDK 3CDK 4CDK 5CDK 6CDK 7CDK 8CDK 9CDK 10CDK 11CDK 12CDK 13Activates a large number of various proteins andleads t

10、o different genes expressionas well as initiatesdifferent phaseof cell cycle.Cyclin D CDK4Cyclin D CDK6Cyclin E CDK2Cyclin A CDK2Cyclin A CDK1Cyclin B CDK1CDKsCDK inhibitors (CKIs) CDK抑制物抑制物Cell cycle progressionCyclins+-CKIslnk4 familyP15P16P18P19Kip/Cip familyP21P27P57CDK inhibitors (CKIs)lnk4 fam

11、ilyP15P16P18P19Kip/Cip familyP21P27P57Inhibit cyclin D/CDK4 and cylcin D/CDK6Universal inhibitorsRetinoblastomaE2FDPCyclinCDKHow does CKI work?CKICKIDNA polymeraseThymidine kinaseCell cycle checkpoints are control mechanisms that ensure the accuracy of cell division. These checkpoints verify whether

12、 the processes at each phase of the cell cycle have been accurately completed before progression into the next phase. Multiple checkpoints have been identified Cell cycle checkpoints 细胞周期检查点细胞周期检查点Mitotic spindle checkpointG1/S checkpoint(Restriction Point)G2/M checkpointCell cycle checkpoints An im

13、portant function of checkpoints is to assess DNA damage, which is detected by sensor（ （探测器探测器） ） mechanisms. When damage is found, the checkpoint uses a signal （ （信号信号） ）mechanism either to stall the cell cycle until repairs are made or, if repairs cannot be made, to target the cell for destruction

14、via apoptosis (effector （ （效应器效应器） ）mechanism). All the checkpoints that assess DNA damage appear to utilize the same sensor-signal-effector mechanism.Mitotic spindle checkpointG1/S checkpoint(Restriction Point)G2/M checkpointCell cycle checkpoints How cell cycle checkpoint worksAtaxia-telangiectasi

15、a mutated (ATM)(Senses DNA double-strand breaks)P53 protein activation(sequence-specific transcriptional factor)Kip/Cip proteins expression (P21, P27, P57)Arrest cell cycle at G1/S transitionAllow DNA repair prior to DNA replicationEffectorSensorTransducerG1SX探测器探测器传感器传感器效应器效应器Regulation of cell pro

16、liferation by extracellular signal细胞外信号对细胞增殖的调控细胞外信号对细胞增殖的调控Many exogenous agents and stimuli are able to regulate cell proliferation: growth factors （ （生长因子生长因子）：）：epidermal growth factor, EGF； ； mitogens（促细胞分裂剂）（促细胞分裂剂） / antimitogens； ； adhesion molecules（粘附分子）（粘附分子）- mediate cell-cell interactio

17、ns, nutrients, etc.Fed with growth agentFed with no growth agentGrowth factor induces cell proliferation Regulation of cell proliferation by extracellular signalMany exogenous agents and stimuli are able to regulate cell proliferation: growth factors (epidermal growth factor, EGF), mitogens / antimi

18、togens, adhesion molecules-mediated cell-cell interactions, nutrients, etc.Cell-cell adhesion induces cell proliferationRegulation of cell proliferation by extracellular signalMany exogenous agents and stimuli are able to regulate cell proliferation: growth factors (epidermal growth factor, EGF), mi

19、togens / antimitogens, adhesion molecules-mediated cell-cell interactions, nutrients, etc.How the extracellular signal regulate cell proliferation?Extracellular agentsSignaling pathwaysCyclin/CDKCell proliferationCKIInhibition of proliferationHow the extracellular signal regulate cell proliferation?

20、Transforming Growth Factor-b b (TGF-b b， ，转化生长因子转化生长因子)Signaling pathwaysCDKCKI (P15,P16,P21,P27)Inhibition of proliferationRetinoblastomaE2FDPP(Example of negative regulation)Cell proliferationDysregulation of cell proliferation and related diseasesDysregulation of cell proliferation is associated

21、withmany diseases: Tumor Inflammatory diseases (Rheumatoid arthritis) Cardiac hypertrophy Vascular proliferative disorders (atherosclerosis)TumorProto-oncogene（ （原癌基因）原癌基因）:A proto-oncogene is a normal gene that can become an oncogene due to mutations or increased expression.The resultant protein is

22、 termed as oncoprotein（ （癌蛋白癌蛋白） ）. Oncogene（ （癌基因癌基因） ）:An oncogene is a gene that has the potential to cause cancer. In tumor cells, oncogenes are often mutated or expressed at high levels. Tumor-suppressor gene（ （肿瘤抑制基因肿瘤抑制基因） ）:A tumor suppressor gene, or anti-oncogene, is a gene that protects a

23、 cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer. Activation of proto-oncogeneThe proto-oncogene can become an oncogene by a relatively small modification of its original function. There are three basic

24、 activation types: 1. A mutation within a proto-oncogene can cause a change in the protein structure, causing1) increase in protein (enzyme) activity,2) loss of regulation (out of control). 2. An increase in protein concentration, caused by protein or mRNA expression.3. A chromosomal translocation,

25、causing an increased gene expression in the wrong cell type or at wrong times. Chromosomal translocationActivation of proto-oncogeneThe proto-oncogene can become an oncogene by a relatively small modification of its original function. There are three basic activation types: 1. A mutation within a pr

26、oto-oncogene can cause a change in the protein structure, causing1) increase in protein (enzyme) activity,2) loss of regulation (out of control). 2. An increase in protein concentration, caused by protein or mRNA expression.3. A chromosomal translocation, causing an increased gene expression in the

27、wrong cell type or at wrong times. Dysregulation of cell proliferation causes tumorGrowth factors,Signal transduction proteins,Transcriptional factors,CyclinsCDKsTumor-suppressor geneslose-of-function mutationDecrease in tumorsuppressive proteins(TGF-b b, CDK inhibitors) Tumor formationProto-oncogen

28、eOncogeneActivation(gain-of-functionMutation) Oncoproteinsover-expression 1) Cyclins, Cyclin-dependent kinases (CDK) and CDK inhibitors (CKIs) 2) Checkpoints 3) Regulation of cell proliferation by extracellular signal.SummaryApoptosis A programmed cell death process regulated by caspases(半胱氨酸天冬氨酸蛋白半

29、胱氨酸天冬氨酸蛋白酶酶 cysteine-aspartic proteases ） ）.Morphological characteristics: DNA and nuclear fragmentation Loss of cell volume Formation of cytoplasmic and membrane blebs (apoptotic body 凋亡小体）凋亡小体）.Apoptosis A programmed cell death process regulated by caspases.Morphological characteristics: DNA and n

30、uclear fragmentation Loss of cell volume Formation of cytoplasmic and membrane blebsApoptotic cells are rapidly removed by neighboring phagocytes without causing inflammationNecrosis A passive unprogrammed cell death process. Morphological characteristics: Persistence of DNA content (no nuclear frag

31、mentation), Increase of cell volume (cell swelling), Rapid loss of plasma and mitochondrial membrane. Necrosis causes inflammationDisruption of plasma membrane and organelles.Numerous lesions appear on the cell surface. A Comparison of Apoptosis and NecrosisApoptosis(programmed)Necrosis(accidental)C

32、aspase-dependent Blebbing of plasma membrane Chromatin condensation Recycling of cellular contentsCaspase-independent Release of cellular contents Loss of plasma membrane No chromatin condensationNon-inflammatoryInflammatoryWebbed fingersWebbed toesApoptosis is an essential process in embryonic deve

33、lopmentRegulation of cell apoptosisInducersRegulatorsEffectorsEffectors of Apoptosis （ （细胞凋亡的执行因子细胞凋亡的执行因子） ）Caspases（ （半胱氨酸天冬氨酸蛋白酶）半胱氨酸天冬氨酸蛋白酶） (cysteine-aspartic proteases ) Endonucleases（ （内源性核酸内切酶内源性核酸内切酶） ）Transglutaminase（ （转谷氨酰胺酶转谷氨酰胺酶） ）Effectors of Apoptosis （ （细胞凋亡的执行因子细胞凋亡的执行因子） ）Caspases

34、（ （半胱氨酸天冬氨酸蛋白酶）半胱氨酸天冬氨酸蛋白酶） (cysteine-aspartic proteases ) Endonucleases（ （内源性核酸内切酶内源性核酸内切酶） ）Transglutaminase（ （转谷氨酰胺酶转谷氨酰胺酶） ）Caspases The caspase family is a group of polymorphic proteases and the central executioners responsible for apoptosis. Eleven human caspases have been discovered. Only 7 o

35、f these are involved in apoptosis. Caspases are synthesized in the cell in an inactive form, which can be activated through different pathways.Caspases can be divided into two groups:initiator caspases caspases 2, 8, 9, 10.effector caspases caspases 3, 6, 7. Regulation of cell apoptosisInducersRegul

36、atorsEffectorsRegulators of ApoptosisApoptosis is tightly regulated by a variety of factors that mainly regulate caspase cascade.1.Mitochondria-derived regulators2. Bcl-2 family proteins3. Inhibitor of apoptosis (IAP) familyRegulators of ApoptosisApoptosis is tightly regulated by a variety of factor

37、s that mainly regulate caspase cascade.1.Mitochondria-derived regulators2. Bcl-2 family proteins3. Inhibitor of apoptosis (IAP) familyRegulators of Apoptosis1.Mitochondria-derived regulators2. Bcl-2 family proteins3. Inhibitor of apoptosis (IAP) familyBcl-2 family proteins Bcl-2 is a family of evolu

38、tionarily conserved proteins. These proteins control mitochondrial outer membrane permeability. Bcl-2 family proteins consist of both anti-apoptotic (antideath) and pro-apoptotic (prodeath) proteins. There are a total of 25 genes in the Bcl-2 family known to date. Bcl-2 family proteinsBH3-onlymolecu

39、lesBax, BakBcl 2The BH3-only family members play a key role in promoting apoptosis. Various apoptotic stimuli induce expression and activation of specific BH3-only family members, which translocate to the mitochondria and initiate Bax/Bak-dependent apoptosis. Role of BH3-only proteinsBH3-onlypro-apo

40、ptoticproteins (Bad, Bid, Bim)Anti-apoptoticproteins (Bcl-2, Bclx, Mcl-1, A1)Multi-domain pro-apoptoticproteins (Bax, Bak)Bcl-2 family protein interactionsApoptosisApoptosisRegulators of Apoptosis1.Mitochondria-derived regulators2. Bcl-2 family proteins3. Inhibitor of apoptosis (IAP) family IAP are

41、a family of proteins that serve as endogenous inhibitors of apoptosis. The human IAP family consists of 8 members. IAP inhibit apoptosis mainly through preventing caspases activation.The Inhibitors of Apoptosis (IAP)ApoptosomeMitochondria-derived regulatorsInner membraneOutermembraneCristaeCytochrom

42、e C(cyt C)Apoptosis-inducing factor (AIF)stressdATPCaspase-9Apaf-1Caspase-3ApoptosisIAPXRegulators of Apoptosis1.Mitochondria-derived regulators2. Bcl-2 family proteins3. Inhibitor of apoptosis (IAP) familyRegulation of cell apoptosisInducersRegulatorsEffectorsInducers of cell apoptosisA wide variet

43、y of pathological cellular insults as well asinternal and external physiological stimuli could trigger apoptosis.1. Apoptosis induced by death signal2. Apoptosis induced by DNA damageInducers of cell apoptosisA wide variety of pathological cellular insults as well asinternal and external physiologic

44、al stimuli could trigger apoptosis.1. Apoptosis induced by death signal2. Apoptosis induced by DNA damageDeath signal is mediated through death receptors (DR).Death receptors are members of the tumor necrosis factor (TNF) receptor (TNFR) superfamily.TNFR superfamily is characterized by a cytoplasmic

45、 region known as the “ “death domain” ” that enables the receptors to initiate cytotoxic signals when bound withcognate ligands. Binding to the ligand results in receptor aggregation and recruitment of adaptor proteins, which, in turn, initiates a proteolytic cascade by recruiting and activating ini

46、tiator caspases, i.e. caspases 8. Death Signal1. TNFR2. Fas: also known as apoptosis antigen 1 (APO-1), CD95 or TNFR superfamily member 6 (TNFRSF6). 3. DR3, DR4, DR5,TNFR SuperfamilyInducers of cell apoptosis1. Apoptosis induced by death signal2. Apoptosis induced by DNA damageHow cell cycle checkpo

47、int worksAtaxia-telangiectasia mutated (ATM)(Senses DNA double-strand breaks)P53 protein activation(sequence-specific transcriptional factor)Kip/Cip proteins expression (P21, P27, P57)Arrest cell cycle at G1/S transitionAllow DNA repair prior to DNA replicationEffectorSensorTransducerG1SXApoptosis i

48、nduced by DNA damageP53 proteinAnti-apoptoticprotein Bcl-2Pro-apoptoticprotein BaxDeath receptorFasMitochondriaCyt C leakageCaspase-3ApoptosisCaspase-9Caspase-8/10DISCformation-+XApoptosis induced by DNA damageP53 proteinAnti-apoptoticprotein Bcl-2Pro-apoptoticprotein BaxDeath receptorFasMitochondri

49、aCyt C leakageCaspase-3ApoptosisCaspase-9Caspase-8/10DISCformation-+XDISCDeath ligandDeath receptorActivecaspase-8/10Extrinsic pathwayApoptosomeRegulation of cell apoptosisCyt CstressdATPCaspase-9Apaf-1Caspase-3ApoptosisIntrinsic pathwayIAP(DNA damage, ROS, etc.)Abnormal cell apoptosis and diseases1

50、. Tumor2. Autoimmune diseases3. Heart FailureAbnormal cell apoptosis and diseasesTumorTumor CellsTumor disappearedApoptosisDefects inApoptosisTumor cellssurvivedTumor cellsGrowthMetastasisChemotherapyRadiationApoptosisTumor disappearedDefects inApoptosisTumor cellssurvivedMechanisms of apoptosis def

51、ects1. Anti-apoptotic protein Bcl-2 over-expression Bcl-2 over-expression was found in B-cell lymphomas and other tumors. Bcl-2 gene is considered as a proto-oncogene2. Chromosome translocation Philadelphia chromosome, a short chromosome 22, results from translocation between chromosome 9 and 22. Th

52、e chimeric gene encoding the fusion protein BCR-ABL suppresses apoptosis in chronic myeloid leukemia (CML) patients.3. P53 gene mutation P53 mutation was found in colorectal carcinoma patients.Dysregulation of cell proliferation Dysregulation of cell apoptosisTumorSummaryDysregulation of cell prolif

53、eration causes tumorGrowth factorsSignal transduction proteinsTranscriptional factorsCyclinsCDKsProto-oncogeneOncogeneActivation(gain-of-functionMutation) Oncoproteinsover-expression Tumor-suppressor geneslose-of-functionmutationDecrease in tumorsuppressive proteins(TGF-b b, CDK inhibitors) Tumor fo

54、rmationTumor CellsTumor disappearedApoptosisDefects inApoptosisTumor cellssurvivedTumor cellsGrowthMetastasisChemotherapyRadiationApoptosisTumor disappearedDefects inApoptosisTumor cellssurvivedDysregulation of cell apoptosis causes tumorDefinition Cell Differentiation is the normal process by which

55、 a less specialized cell develops or matures to possess a more distinct form (structure) and function. Stem cellsStem cells have the remarkable potential to develop into many different cell types in the body during early life and growth. In many tissues stem cells serve as a internal repair system,

56、dividing essentially without limit to replenish other cells as long as the person or animal is still alive. Stem cells Proliferation (Self-renewal)Differentiation Lineage(A single cell type)Multipotenta variety of cell typesSymmetric division Asymmetric division Regulation of Cell Differentiation1.

57、Intracellular regulators2. DNA methylation3. Extracellular factorsRegulation of Cell Differentiation1. Intracellular regulators2. DNA methylation3. Extracellular factorsHomeotic genes are genes that determine which parts of the body form what body parts; and where, when, and how body segments develo

58、p. Alterations in these genes cause changes in patterns of body parts.Homeotic genesIntracellular regulatorsHomeotic genes(a small number of master regulatory genes)ExtracellularfactorsTranscriptionalfactorsGene productsCell receptorParticular genesexpressionDifferentiationRegulation of Cell Differe

59、ntiation1. Intracellular regulators2. DNA methylation3. Extracellular factorsTFParticular genes expressionand cell differentiationmmTFParticular genes expressionis blocked andno differentiation occurs.DNA methylationRegulation of Cell Differentiation1. Intracellular regulators2. DNA methylation3. Ex

60、tracellular factorsExtracellular factors1. Cell-cell interaction2. Cell-ECM (extracellular matrix) interaction3. Growth factors:1) EGFs (epidermal growth factor)2) TGFb (b (transforming growth factor-b)-b)3) IGF-1 (Insulin-like growth factor-1)4. Hematopoietic factors: G-CSF (granulocyte colony-stim