Abnormal Cell Abnormal Cell Proliferation,Differentiation Proliferation,Differentiation Apoptosis and Related Disease Apoptosis and Related Disease Department of Pathophysiology Department of Pathophysiology Shanghai Jiao-Tong University School o Shanghai Jiao-Tong University School o f Medicine f Medicine
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Abnormal Cell Proliferation,Differentiation Apoptosis and Related Disease Department of Pathophysiology Shanghai Jiao-Tong University School of Medicine.
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Abnormal Cell Proliferation,Differentiation Abnormal Cell Proliferation,Differentiation Apoptosis and Related DiseaseApoptosis and Related Disease
Department of PathophysiologyDepartment of Pathophysiology
Shanghai Jiao-Tong University School of MedicineShanghai Jiao-Tong University School of Medicine
Evan, GI and Vousden, K. (2001) Nature 411:342
The Cancer Problem
Proliferation Differentiation
Apoptosis
Cell
【【 Cell ProliferationCell Proliferation 】】 Cell proliferation is a process of cell division and regeneration, Cell proliferation is a process of cell division and regeneration, which results in an increase in the cell number with exact passages which results in an increase in the cell number with exact passages of genetic information to their daughter cells.of genetic information to their daughter cells.
Abnormal Cell Proliferation and DiseasesAbnormal Cell Proliferation and Diseases
Phase of cell cycle
• M-Phase– Mitosis– Cytokinesis
• Interphase– G1 = Gap between M and S– S = Synthesis (DNA and cen
trosomes replicated)– G2 = Gap between S and M
Interphase Prophase Prometaphase Metaphase
Anaphase Telophase Cytokinesis
Mitosis
2001 Nobel Prize
Leland H. Hartwell 1970s“Checkpoint”Yeast genetics~100 CDC genesStart gene
Tim Hunt 1980sCyclinsSea Urchins
Paul M. Nurse1970sCDKsyeast
Cell Cycle Regulation
• Cyclins
• Cyclin Dependent Kinases (CDKs)
• Cyclin Dependent Kinases Inhibitors (CDKIS)
●●CyclinCyclin
【【 Classification Classification 】】
Cyclin B1Cyclin B1 、、 Cyclin ACyclin A 、、 Cyclin ECyclin E 、、 Cyclin DCyclin D11,D,D22,D,D33. . FF,,G,H,TG,H,T. .
Cyclin Protein kinase process regulated
Cyclin D1-3 Cdk 4,6 G1-phase progression
Cyclin E Cdk2 G1 to S-phase
Cyclin A Cdk2 S-phase progression
Cyclin A Cdk1 S through G2
Cyclin B Cdk1 M-phase
Cyclic Degradation:
Ubiquitin-mediated breakdown by Proteasome
Experimental Demonstration that Cyclin D is Required for Passage Through the Restriction Point in the Mammalian Cell
Deregulation of cell cycle causes cell proliferation excessive or insufficDeregulation of cell cycle causes cell proliferation excessive or insufficency.ency.
【【 Deregulation of cell cycleDeregulation of cell cycle 】】
■■loss of control in driving cell cycle progression(Cyclin,CDK,CDIloss of control in driving cell cycle progression(Cyclin,CDK,CDI ))■■The impairment of checkpoint systemThe impairment of checkpoint system
Malignant tumorMalignant tumor
Cancer is a disease where regulation of the cell cycle goes
awry and normal cell growth and behavior is lost .
11 . . loss of control in driving cell cycle progressionloss of control in driving cell cycle progression
■ ■ Overexpression of cyclinsOverexpression of cyclins
▲loss of Gloss of G22/M checkpoint chromosome rearrangement, loss/M checkpoint chromosome rearrangement, loss
Primary ThrobocythemiaPrimary Throbocythemia
■ ■ clinical clinical symptomssymptoms :: is characterized by a platelet count greateis characterized by a platelet count greater than 600,000/µL, megakaryocytic hyperplasia, splenomegaly, r than 600,000/µL, megakaryocytic hyperplasia, splenomegaly, and a clinical course complicated by thrombotic and/or hemorrhand a clinical course complicated by thrombotic and/or hemorrhagic episodesagic episodes.
■■ The cause of ET is not fully understood. About half of patients with ET have a mutation of the JAK2 (Janus kinase 2) gene in their blood cells. Whether or not a patient has the mutation 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 ET patients.
Apoptosis is a genetically controlled process regulated by complApoptosis is a genetically controlled process regulated by complex molecular signaling systems.ex molecular signaling systems. It is also known as cellular self destruction or cell-suicide or programmed cell death (PCD).
1. Extrinsic or cytoplasmic pathway1. Extrinsic or cytoplasmic pathway
■■Death receptor TNFR, FasR, DRDeath receptor TNFR, FasR, DR33,, DRDR44,, DRDR55,,The DR family is part of the tumor necrosis factor receptor superfamily. Triggering members of the DR family by death ligands results in the transduction of either apoptotic or survival signals.
Mechanism of calcium overload Mechanism of calcium overload induced apoptosisinduced apoptosis
apoptosis
Mechanism of apoptosisMechanism of apoptosis
11 .. Oxidation damage Oxidation damage
Oxygen free radicals disrupt the normal redox equilibrium, result in the Oxygen free radicals disrupt the normal redox equilibrium, result in the injuring of protein,lipid and DNA.injuring of protein,lipid and DNA.
【【 MechanismMechanism 】】
Activation of Activation of p53, consuming of ATP, membrane lipid peroxidation, acp53, consuming of ATP, membrane lipid peroxidation, activation of endonuclease, initiating apoptosistivation of endonuclease, initiating apoptosis ..
■■ P53 relocalizes Fas to cell membrane.P53 relocalizes Fas to cell membrane.
22 .. pp5353 (( tumor suppressor genetumor suppressor gene )) As a transcription factor, p53 regulates downstream genes impAs a transcription factor, p53 regulates downstream genes important in cell cycle arrest, DNA repair, and apoptosis. After DNA dortant in cell cycle arrest, DNA repair, and apoptosis. After DNA damage, p53 holds the cell at a checkpoint until the damage is repamage, p53 holds the cell at a checkpoint until the damage is repaired. If the damage is irreversible, apoptosis is triggered.aired. If the damage is irreversible, apoptosis is triggered.
Table . Human diseases associated with disordered apoptosis
Decreased Apoptosis Increased Apoptosis
Epithelial Tissue
Carcinogenesis Macrophages
Bacillary dysentery
Blood Vessels Intimal hyperplasia Myocardium Peri-infarct border zones
Lymphocytes Autoimmune disorders
Lymphocytes lymphocytes depletion in HIV injections and sepsis
Haemopoeitic systems
Leukemia, lymphoma
CNS Neurodegenerative diseases like Alzheimer’s and Parkinson’s disease
■■ bcl-2 overexpressionbcl-2 overexpression
In follicular lymphoma, a chromosomal translocation commonly occurs between the In follicular lymphoma, a chromosomal translocation commonly occurs between the
fourteenth and the eighteenth chromosomes-t(14;18)-which places the Bcl-2 gene nefourteenth and the eighteenth chromosomes-t(14;18)-which places the Bcl-2 gene ne
xt to the immunoglobulin heavy chain locus. This fusion gene is deregulated, leading xt to the immunoglobulin heavy chain locus. This fusion gene is deregulated, leading
to the transcription of excessively high levels of bcl-2. This decreases the propensity to the transcription of excessively high levels of bcl-2. This decreases the propensity
of these cells for undergoing apoptosis.of these cells for undergoing apoptosis.
(( also observed in breast cancer, lung cancer, malanoma, prostate cancealso observed in breast cancer, lung cancer, malanoma, prostate cance
rr ))■■ pp53 deletion or mutation53 deletion or mutation
Abnormal of P53 in stability, localization or activationAbnormal of P53 in stability, localization or activation
pp53 expression or function defect apoptosis rate↓ tumorgenesis 53 expression or function defect apoptosis rate↓ tumorgenesis
( ( abnormal P53 observed in at least 50% malignant cancerabnormal P53 observed in at least 50% malignant cancer ))
HBV encoded HBHBV encoded HBX X is inhibitor for Caspase-3, and is associated with livis inhibitor for Caspase-3, and is associated with liv
er cancer.er cancer.
22 .. Autoimmune diseasesAutoimmune diseases
A common feature of autoimmune diseases is the breakdown of tA common feature of autoimmune diseases is the breakdown of tolerance of self antigens, a consequence of which is the productiolerance of self antigens, a consequence of which is the production of autoantibodies reactive with multiple self proteins. Defect on of autoantibodies reactive with multiple self proteins. Defect in apoptosis can cause autoimmunity by allowing the survival of in apoptosis can cause autoimmunity by allowing the survival of autoreactive T and B cells. autoreactive T and B cells.
Deregulated cell differentiation and Deregulated cell differentiation and Disease Disease
►►ConceptConcept
Cell differentiation is a process in which a generic cell develoCell differentiation is a process in which a generic cell develops into different kinds cells with the specialized morphology, metaps into different kinds cells with the specialized morphology, metabolism and physiological functions in response to specific triggers bolism and physiological functions in response to specific triggers from the body or the cell itself.from the body or the cell itself.
Cell differentiation is tightly regulated by a series of regulatory Cell differentiation is tightly regulated by a series of regulatory
proteins.proteins.
Ey gene in the Ey gene in the morphogenesis of eyesmorphogenesis of eyes
Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors
Determination and differentiationDetermination and differentiation
The The determinationdetermination of different cell types (cell fates) involves of different cell types (cell fates) involves progressive restrictions in their developmental potentials. Wheprogressive restrictions in their developmental potentials. When a cell “chooses” a particular fate, it is said to be determined, n a cell “chooses” a particular fate, it is said to be determined, although it still "looks" just like its undetermined neighbors. Dalthough it still "looks" just like its undetermined neighbors. Determination implies a stable change - the fate of determined cetermination implies a stable change - the fate of determined cells does not change.ells does not change. Differentiation follows determination.
In some cases, determination results from the asymmetric segregation of cellular determinants. However, in most cases, determination is the result of inductive signaling between cells.
2. Regulation on transcription and post- transcription level2. Regulation on transcription and post- transcription levelss ))
The regulation of cell differentiationThe regulation of cell differentiation
1. Regulation on the genomic level1. Regulation on the genomic level ))
■■ House-keeping genesHouse-keeping genes
House-keeping genes generally encode proteins that House-keeping genes generally encode proteins that participate in basic or universal cellular functions essential for participate in basic or universal cellular functions essential for maintaining cell survival.maintaining cell survival.
■ ■tissue specific genetissue specific gene
3. tranlational and post-translational level3. tranlational and post-translational level
4. Extracellular factors that control differentiation4. Extracellular factors that control differentiation
Hem
atopoiesis
acute promyelocytic leukemia
“Acute promyelocytic leukemia (AML M3) is now the
most frequently curable acute leukaemia in adults if
promptly diagnosed and adequately treated.”Parmar S, Tallman MS. , 2003
1988: Breakthrough in treatment from China
1990: Multiple groups identify RAR as t(15; 17) breakpoint
How does ATRA induce remission?
How does PML-RAR induce APL?
Drug Gene
Morbid obesityMorbid obesity
Excess pre-adipocyte differentiate into adipocyte.Excess pre-adipocyte differentiate into adipocyte.