MITOSIS AND CYTOKINESIS Marie Kopecká 2006/2007mkopecka@med.muni.cz
In a typical eukaryotic somatic cellMITOSIS= NUCLEAR DIVISIONCYTOKINESIS = DIVISION OF THE CYTOPLASM.IMPORTANCE OF MITOSIS...
Rudolf VIRCHOW (1858): „OMNIS CELLULA E CELLULA”„ALL CELLS DERIVED FROM CELLS”        How    ?
1590 Z. and J. Janssen: light microscope1665 R. Hook: first observation of cells1674 A. v. Leeuwenhoek: microorganisms1833...
Carl and Gerta CORI, the 1947 Nobel LaureatesThe origin of protein phosphorylation: PROTEINKINASES   From Cohen, Nature Ce...
The mechanisms of M-phase progression:  • Protein phosphorylation    protein kinases  •   Protein defosforylation      pro...
EUKARYOTIC CELL DIVISION CYCLE G1 S G2 MEach stage triggered by Cyclin dependent kinase(s)+Cyclin(s),M-phase by Cdc2/CycB=...
Nobel price for Physiology and Medicine (2001) for „Discovery of Key Regulators of Cell Division Cycle”L. Hartwell 1960→bu...
CDC28                                 mutant                                 blocked at                                 th...
From Nurse,Nobel Lecture
CDK1Cdc2=catalytic subunit of mitotic kinase in humans
Mitotic kinase (MPF=CDK1): Catalytic subunitjoins cyclin regulatorysubunit. It is phosporylatedat two sites. Activation of...
How the mitotic kinase Cdc2/CycB (=CDK1) is activated?Inactive mitotic kinase CDK1→Activated CDK1                         ...
Mitotic kinases – regulators of M-phase and its checkpoints                                    Nigg
INTERPHASE – preparing for M-phaseG1: cell growth;  preparing for S phaseS: cell growth;synthesis of nuclear DNA;synthesis...
1914 Th. Boveri: the cell consists of the cytoplasm, nucleus and the centrosome  From Pederson, Nature Cell Biol  2006
Meraldi P., Nigg E., Centrosome duplication, maturation and separationFEBS Letters (2002)                                 ...
POLOKINASE mutants have aberrant mitoticspindles (e.g. monopolar or multipolar).Some cancer cells have multipolar spindles...
Interphase---→M-phase:                   Mitosis (5 stages) →Cytokinesis    Interphase          1. Prophase           2. P...
G2 CHECKPOINT (G2/M) :     DNA damaged? DNA replication completed?...When DNA is dama-ged or incompletelyreplicated,Checkp...
Prophase: reorganisation of nucleus and cytoplasm during mitosis isinduced by activated Cdk1-cyclin complexes and other ki...
Prometaphase                             PrometaphaseEach chromatid has   Microtubules joinits kinetochore in   kinetochor...
Metaphase                        Centrosomes are                        at opposite poles.                         Mitotic...
DIC                                           IF1882 W. Flemming  From Nurse, Cell 100, 2000         TEM
From Clarke, Giménez-Abian, BioEssays 2000
Metaphase checkpoint („spindle assembly checkpoint”)Are all chromosomes joined to mitotic spindle?                        ...
How Anaphase is started:1. Anaphase Promoting Complex (APC).2. APC ubiquitinates and induces disruption   of inhibitor „SE...
A   B
Inactivation of mitotic   Telophase,CDK1 in anaphase leadsto telophase and                          Cytokinesiscytokinesis...
CYTOKINESIS IN ANIMAL CELL
Cytokinesis in plant cell (ELM)Phragmoplast
Cytokinesis in bacteria- FtsZ ring Addinal and Holland,J Mol Biol 2002
CYTOKINESIS IN ANIMAL and    CYTOKINESIS IN PLANT CELLFUNGAL CELL                 CYTOKINESIS IN PLANT CELL               ...
Cytokinesis is triggered by Rho-GTPase               From Narumiya and Yasuda,                       (2006)
Medical applications of theknowledge on the dynamics ofmicrotubules in mitosis intherapy of cancers:Microtubule inhibitors...
Further strategy: Looking for CDK inhibitors From Meijer and Raymond, Acc.Chem Res. (2003)
olomoucine
Mitotic kinase Cdk1-cyclin in G2 checkpoint and Metaphase checkpoint          G2 checkpoint                          Metap...
Specific termsMITOSIS The process of nuclear division.CYTOKINESIS The process of cytoplasmic division.CENTROSOME The main ...
L10 mitosis cytokinesis_eng
L10 mitosis cytokinesis_eng
L10 mitosis cytokinesis_eng
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L10 mitosis cytokinesis_eng

  1. 1. MITOSIS AND CYTOKINESIS Marie Kopecká 2006/2007mkopecka@med.muni.cz
  2. 2. In a typical eukaryotic somatic cellMITOSIS= NUCLEAR DIVISIONCYTOKINESIS = DIVISION OF THE CYTOPLASM.IMPORTANCE OF MITOSIS:EXACT SEPARATION OF REPLICATEDGENOME into two originating daughter cells→ origin of genetically identical daughter cells.Inheritance of CENTROSOME.IMPORTANCE OF CYTOKINESIS:Inheritance of corresponding part of the CYTOPLASMand CELL ORGANELLES.
  3. 3. Rudolf VIRCHOW (1858): „OMNIS CELLULA E CELLULA”„ALL CELLS DERIVED FROM CELLS” How ?
  4. 4. 1590 Z. and J. Janssen: light microscope1665 R. Hook: first observation of cells1674 A. v. Leeuwenhoek: microorganisms1833 Brown: cell nucleus1838 M. J. Schleiden, T. Schwan: cell theory1839 J.E.Purkyně: cell theory1866 J. G. Mendel: element (gene)1869 F. Miescher: DNA1911 J. H.Morgan: genes in chromosomes1879 W. Flemming: chromosomes during mitosis1884 Strasburger: prophase, metaphase…1888 Waldeyer: chromosome1933 E. Ruska: first transmission electron microscope1953 J. Watson, F. Crick: structure of DNA1973 L. Hartwell: genes of the cell division cycle (cdc28)1989 P. Nurse: genes of mitotic pathway in yeast (cdc2)
  5. 5. Carl and Gerta CORI, the 1947 Nobel LaureatesThe origin of protein phosphorylation: PROTEINKINASES From Cohen, Nature Cell Biol 2002
  6. 6. The mechanisms of M-phase progression: • Protein phosphorylation protein kinases • Protein defosforylation protein phosphatases • Proteolysis (protein degradation) ubiquitination→proteasomes • Rho-GTPases
  7. 7. EUKARYOTIC CELL DIVISION CYCLE G1 S G2 MEach stage triggered by Cyclin dependent kinase(s)+Cyclin(s),M-phase by Cdc2/CycB=Mitotic Kinase=CDK1 -phase interphase
  8. 8. Nobel price for Physiology and Medicine (2001) for „Discovery of Key Regulators of Cell Division Cycle”L. Hartwell 1960→budding yeast (cdc28 gene and others).P. Nurse 1970→fission yeast (cdc2 gene of mitotic kinase).T.Hunt - biochemist →discovered cyclins
  9. 9. CDC28 mutant blocked at the STARTcdc2 Cdc2 mutant blocked at mitosis Nurse Hartwell
  10. 10. From Nurse,Nobel Lecture
  11. 11. CDK1Cdc2=catalytic subunit of mitotic kinase in humans
  12. 12. Mitotic kinase (MPF=CDK1): Catalytic subunitjoins cyclin regulatorysubunit. It is phosporylatedat two sites. Activation ofMPF requires removal ofinhibitory phosphate by
  13. 13. How the mitotic kinase Cdc2/CycB (=CDK1) is activated?Inactive mitotic kinase CDK1→Activated CDK1 Mitosis → Cytokinesis - Activating kinaseMitotic kinase=CDK1Catalytic subunit Regulatory subunit Inhibitory kinase Activating phosphatase
  14. 14. Mitotic kinases – regulators of M-phase and its checkpoints Nigg
  15. 15. INTERPHASE – preparing for M-phaseG1: cell growth; preparing for S phaseS: cell growth;synthesis of nuclear DNA;synthesis of histones;sister chromatids joined by cohesins;duplication of centrosomes.G2: cell growth;preparing for M-phase.
  16. 16. 1914 Th. Boveri: the cell consists of the cytoplasm, nucleus and the centrosome From Pederson, Nature Cell Biol 2006
  17. 17. Meraldi P., Nigg E., Centrosome duplication, maturation and separationFEBS Letters (2002) Polokinasa,Aurora kinasa.. Cdk1, Polokinasa, Nek2… Cdk2/Cyclin E,A
  18. 18. POLOKINASE mutants have aberrant mitoticspindles (e.g. monopolar or multipolar).Some cancer cells have multipolar spindles andmultiple centrosomes.From Glover et al., J.Cell Biol. 1996
  19. 19. Interphase---→M-phase: Mitosis (5 stages) →Cytokinesis Interphase 1. Prophase 2. Prometaphase 3. Metaphase 4. Anaphase 5. Telophase Cytokinesis Zdroj: AF ÚG MZLU
  20. 20. G2 CHECKPOINT (G2/M) : DNA damaged? DNA replication completed?...When DNA is dama-ged or incompletelyreplicated,Checkpoint kinasesCHK1 or CHK2 switchon inhibitory pathwayto block cell cycle byinhibiting mitotickinase Cdk1/Cyclin Band phosphatasecdc25C. Whencompleted, Cdc25C isreleased to activatemitotic kinaseCdk1/Cyclin B.
  21. 21. Prophase: reorganisation of nucleus and cytoplasm during mitosis isinduced by activated Cdk1-cyclin complexes and other kinases thatphosphorylate numerous substrates: nuclear lamins, condensins, histonesH1, H3, MAPs, motor proteins, centrosomes, Golgi apparatus… ProphaseDisappearance ofnuclear envelope Mitotic spindle originate between separating centrosomes.Chromosomes consist of two identical sister Nucleolichromatids joined by cohesins. disappear.Condensation of chromosomes – condensins.
  22. 22. Prometaphase PrometaphaseEach chromatid has Microtubules joinits kinetochore in kinetochorescentromere region. Nuclear envelope disappears
  23. 23. Metaphase Centrosomes are at opposite poles. Mitotic apparatus consists of astral, polar and kinetochore microtubules. Chromosomes are at „metaphase plate” in the equatorial plane.Kinetochores of sisterchromatids of each chromosomejoined to microtubules directedto opposite poles of the spindle.
  24. 24. DIC IF1882 W. Flemming From Nurse, Cell 100, 2000 TEM
  25. 25. From Clarke, Giménez-Abian, BioEssays 2000
  26. 26. Metaphase checkpoint („spindle assembly checkpoint”)Are all chromosomes joined to mitotic spindle? NO → checkpoint activated → kinetochore signaling ⇒STOP ANAPHASE! YES →checkpoint silenced → ANAPHASE
  27. 27. How Anaphase is started:1. Anaphase Promoting Complex (APC).2. APC ubiquitinates and induces disruption of inhibitor „SECURIN” that inhibited protease „SEPARASE”.3. SEPARASE digests protein “COHESIN” joining sister chromatids4. Sister chromatids separate and are pulled to opposite poles of the spindle5. APC induces disruption of M-phase cyclin B→ inactivation of M-Cdk→cytokinesis
  28. 28. A B
  29. 29. Inactivation of mitotic Telophase,CDK1 in anaphase leadsto telophase and Cytokinesiscytokinesis:- Daughter nuclei at opposite poles.- Nuclear envelopes formed again.- Chromosomes decondense.- Mitotic apparatus disappears.- Cytokinesis starts.
  30. 30. CYTOKINESIS IN ANIMAL CELL
  31. 31. Cytokinesis in plant cell (ELM)Phragmoplast
  32. 32. Cytokinesis in bacteria- FtsZ ring Addinal and Holland,J Mol Biol 2002
  33. 33. CYTOKINESIS IN ANIMAL and CYTOKINESIS IN PLANT CELLFUNGAL CELL CYTOKINESIS IN PLANT CELL CYTOKINESIS IN BACTERIA – FtsZ ring
  34. 34. Cytokinesis is triggered by Rho-GTPase From Narumiya and Yasuda, (2006)
  35. 35. Medical applications of theknowledge on the dynamics ofmicrotubules in mitosis intherapy of cancers:Microtubule inhibitors TAXOLE,VINCRISTINE, VINBLASTINE…inhibit dynamic instability ofmicrotubules → block mitosesand inhibited cells die….
  36. 36. Further strategy: Looking for CDK inhibitors From Meijer and Raymond, Acc.Chem Res. (2003)
  37. 37. olomoucine
  38. 38. Mitotic kinase Cdk1-cyclin in G2 checkpoint and Metaphase checkpoint G2 checkpoint Metaphase checkpoint Nigg
  39. 39. Specific termsMITOSIS The process of nuclear division.CYTOKINESIS The process of cytoplasmic division.CENTROSOME The main microtubule-organizing centre of animal cells.MITOTIC SPINDLE A highly dynamic bipolar array of microtubules that form during mitosis or meiosis and serves to move duplicated chromosomes apart.SISTER CHROMATID Duplicated chromosomes.CHECKPOINT A point where the cell division cycle can be halted until conditions are suitable for the cell to proceed to the next stage.NUCLEAR LAMINA A nuclear membrane-associated protein structure made up of lamin intermediate filament proteins.KINESIN Microtubule-based molecular motor, most often directed towards the plus end of microtubules.DYNEIN Microtubule-based molecular motor that moves towards the minus end of microtubules.GAMA-TUBULIN RING COMPLEXES Ring-like multiprotein structures implicated in microtubule nucleation.KINETOCHORE Specialized assembly of proteins that binds to a region of the chromosomes called centromere.CENTROMERE A region of eukaryotic chromosome that is attached to the mitotic spindle.

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