病理学与病理生理学：11cell proliferationapoptosis and related disease

1、The Cancer ProblemEvan, GI and Vousden, K. (2001) Nature 411:342Colon cancer xenograftCellDifferentiationApoptosisProliferationTumorigenesisCell Proliferation M-Phase Mitosis Cytokinesis Interphase G1 = Gap between M and S S = Synthesis (DNA and centrosomes replicated) G2 = Gap between S and MCell c

2、ycle is defined as a period from the end of one division to the end of next division of a proliferative cellCell CycleInterphase Prophase Prometaphase Metaphase AnaphaseTelophase Cytokinesis MitosisLeland H. Hartwell 1970s“Checkpoint”Yeast genetics100 CDC genesStart geneTim Hunt 1980sCyclinsSea Urch

3、insPaul M. Nurse1970sCDKsyeast The Nobel Prize in Physiology or Medicine 2001Leland HartwellCDC（Cell Division Cycle）CDC28: start first CDK (Cyclin Dependent Dinase)checkpoint Saccharomyces cerevisiae Paul NurseSaccharymtces pombeCdc2CDK1Tim HuntArbacia punctulata Cyclin ACyclin B Cyclins Cyclin Depe

4、ndent Kinases (CDKs) Cyclin Dependent Kinases Inhibitors (CDKIS)Cell Cycle Regulation Cyclin Proteinkinaseprocess regulatedCyclin D1-3Cdk 4,6G1-phase progressionCyclin ECdk2G1 to S-phase Cyclin ACdk2S-phase progression Cyclin ACdk1S through G2 Cyclin BCdk1M-phase Experimental Demonstration that Cycl

5、in D is Required for Passage Through the Restriction Point in the Mammalian Cell Cyclin DegradationUbiquitin-mediated breakdown by ProteasomePolyubiquitination of mitotic cyclin泛素泛素蛋白质蛋白质降解的蛋白质降解的蛋白质Cyclin Dependent Kinase (CDK) PSTAIRE Thr14、Tyr15 dephorsphorylation CDK activation (CAK)Cyclin HCDK7

6、P36Cdc25CAKCdc25ARS-autonomously replication sequences Cyclin Dependent Kinases Inhibitor (CKI) In response to DNA damage in G1, the protein level of p53 rises dramatically due to the activation of a checkpoint protein kinase (chk2) that phosphorylate p53 and make it less susceptible to degradation

7、by the ubiquitination/proteasome pathway. This enables p53 to activate transcription of the cdk inhibitor (CKI) p21 which binds to all cdks and inhibits their action and thus “arrests” the cells until the DNA damage can be repaired. Ataxia telangiectasia mutated pRb E2F（EGF、IGF、IL）aplastic anemiaobe

8、sitymalignant tumorleucodermaheritage hemoglobinopathypsoriasisprostatic hypertrophy muscular dystrophy dysembryomscleratheromacongenital deformityFamilial erythrocytosis X-linked hyper IgM syndrome Cancer is a disease where regulation of the cell cycle goes away and normal cell growth and behavior

9、is lost Table 8.3 The Biology of Cancer ( Garland Science 2007)Table 8.4 The Biology of Cancer ( Garland Science 2007) .The cause of PT is not fully understood. About half of patients with PT have a mutation of the JAK2 (Janus kinase 2) gene in their blood cells. Whether or not a patient has the mut

10、ation does not appear to affect the nature or course of the disease. Research is under way to determine the precise role of JAK2 mutations and to identify other mutations in PT patients.Aplastic Anemia bone marrow hematopoietic stem cell Aplastic anemia is a syndrome of bone marrow failure character

11、ized by peripheral pancytopenia and marrow hypoplasia. Although the anemia is often normocytic, mild macrocytosis can also be observed in association with stress erythropoiesis and elevated fetal hemoglobin levels.On morphologic evaluation, the hematopoietic elements in the bone marrow are less than

12、 25%, and they are largely replaced with fat cells. Flow cytometry shows that the CD34 positive cell population, which contains the stem cells and the early committed progenitors, is substantially reducedApoptosis It is also known as cellular self destruction or cell-suicide or programmed cell death

13、 (PCD). Adaptation and injury of cell and tissueBy Fu Guo-huiIn humans, as many as 1011 cells die in each adult each day and are replaced by other cells. The mass of cells we lose each year is close to our entire body weight!“for their discoveries concerning genetic regulation for their discoveries

14、concerning genetic regulation of organ development and of organ development and programmed cell deathprogrammed cell death”1090 131= 959(cells)Robert HorvitzJohn SulstonSydney BrennerPhysiology or Medicine Nobel Prize 2002He chose the nematode because of its short life cycle, genetic simplicity and

15、tiny size less than 1 mm long”ced-1,ced-2 , nuc-1ced-3, ced-4 apoptotic cell (SEM) (TEM)Morphological features of Morphological features of apoptosisapoptosisMembrane blebbing Caspase (cysteine-containing aspartate-specific protease)Inducers InhibitorsPhysical and chemical factorsIrradiation, high t

16、emperature, stress, chemotherapeutic drugscytokinesIL-2、NGFHormone and cytokinesGlucocorticoid, TNFhormone ACTH, testosterone, estrogenImmunitygranzymeothersZn2+、agrypnal、cystein protease inhibitor, EBV, cowpox, virus, neutral amino acidpathogenHCV, HIVInteraction of large and small subunit （dimer）

17、caspase activation（tetramer） Pro-caspase： NH2 terminal domain、 20KD subunit、 10KD subunit cleavageUpstream CaspaseDownstream CaspasePro-Caspase-3The DR family is part of the tumor necrosis factor receptor superfamily. Triggering members of the DR family by death ligands results in the transduction o

18、f either apoptotic or survival signals.TNFR familyTNFRFas（APO-1或CD95）DR3（APO-3、TRAMP、LARD或wsl-1）DR4（TRAIL-R1）DR5（APO-2、TRAIL-R2、KILLER） TRAIL:TNF-related apoptosis inducing ligand FasFas LFADDTNF-R1-Associated Death Domain TNF Receptor-Associated Factor 2 , can lead to activation of NF-kB and the JN

19、K pathway. Apoptosis inducerIntrinsic or Mitochondrial PathwayMitochondrial energy productionPTP - permeability transition pore MMP-Mitochondrial membrane permeability transition poreApaf-1Cytochrome CATPATPPro-casp-9Pro-caspase 3caspase 3Pro-casp-9caspase recruitment domain，CARD Pro-casp-9apoptosom

20、ewheel of death 凋亡诱导因子（apoptosis-inducing factor, AIF） Smac/DIABLO （second mitochondria-derived activators of caspase/direct IAP-binding protein with a low isoelectric points）核酸内切酶G（endonuclease G，Endo G）Apaf-1Cytochrome CATPATPPro-casp-9Pro-caspase 3caspase 3Pro-casp-9caspase recruitment domain，CAR

21、D Pro-casp-9apoptosome apoptosisBcl-2+caspase-independent apoptosisapoptosisTable . Human diseases associated with disordered apoptosisDecreased ApoptosisIncreased ApoptosisEpithelial TissueCarcinogenesisMacrophagesBacillary dysenteryBlood VesselsIntimal hyperplasiaMyocardiumPeri-infarct border zone

22、sLymphocytesAutoimmune disordersLymphocytes lymphocytes depletion in HIV injections and sepsisHaemopoeitic systemsLeukemia, lymphomaCNSNeurodegenerative diseases like Alzheimers and Parkinsons disease Systemic lupus erythematosus (SLE) may cause a distinctive butterfly-shaped rash on the face. Fas d

23、yregulation,bcl-2 overexpressionFas dyregulation,bcl-2 overexpression 2. Alzheimers Disease，ADAlzheimers disease is characterised by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This loss results in gross atrophy of the affected regions, including degeneration

24、 in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus .Degeneration is also present in brainstem nuclei like the locus coeruleus. HIV InfectionReceptor for HIV-I and HIV-2 gp120Receptor for HIV-I and HIV-2 gp120 Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined FactorsCell 2007,131,861-872 （Oct3/4