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Cell cycle deregulation and cardiovascular diseases

Cell cycle deregulation and cardiovascular diseases. Ana Rita Lobo Diogo Matos Inês Matos. Objectives. Cell cycle Interphase Mitosis Control System of the Cell Cycle Cell cycle machinery and Stroke. Cell Cycle.

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Cell cycle deregulation and cardiovascular diseases

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  1. Cellcyclederegulationand cardiovascular diseases Ana Rita Lobo Diogo Matos Inês Matos

  2. Objectives • Cellcycle • Interphase • Mitosis • ControlSystemoftheCellCycle • CellcyclemachineryandStroke

  3. CellCycle • The cell cycle is the series of events which take place in the cell and lead to its duplication by means of replication and duplication of its previous contents.

  4. Cellcycle’sphases • The cell cycle is generally divided into two phases: • Interphase - the cell spends most of its time performing the functions that make it unique. • Mitosis - the cell divides into two daughter cells.

  5. Interphase • The interphase stage of the cell cycle includes three distinctive parts: • G1phase- follows mitosis and is the period in which the cell is synthesizing its structural proteins and enzymes to perform its functions; • S phase-the DNA within the nucleus replicates • G2phase-the cell prepares for mitosis. Proteins organize themselves to form a series of fibers called the spindle, which is essential to chromosome movement during mitosis

  6. MitoticPhase • Themitoticphaseistheperiod in thecellcyclewhereoccurs, thenucleousdivision. Themitoticprocessincludes 4 phases: • Prophase • Metaphase • Anaphase • Telophase • Afterthemitoticphase, thecytokinesisoccurs: microfilaments contract during cleavage and assist the division of the cell into two daughter cells.

  7. ControlSystemoftheCellCycle • In themajorityofeukaryoticcells, thecontrolsystemsofthecellcycleactivateitsprogression in threepoints.

  8. ControlSystemoftheCellCycle Elementsinvolved: • Cyclins-dependentkinases (CDKs) • Cyclins • CDK inhibitorproteins (CKIs) • Retinoblastoma protein (Rb) • CyclicalProteolysis

  9. CDKs CYCLINS • Cyclins are a family of proteins that have no enzymatic activity of their own but activate CDKs by binding to them. • Themaincomponentsofthecontrolsystemofthecellcycle are a memberof a kinases’ familyknown as cyclin-dependentkinasesthat can modify various protein substrates involved in cell cycle progression. Cyclin Cyclindependtkinase (CDK)

  10. How Do CDKs Control the Cell Cycle? • All cyclins are named according to the stage at which they assemble with CDKs. Common classes of cyclins include G1/S-phase cyclins, S-phase cyclins, and M-phase cyclins. • Because cyclin-CDK complexes recognize multiple substrates, they are able to coordinate the multiple events that occur during each phase of the cell cycle.

  11. How Do CDKs Control the Cell Cycle?

  12. InhibitorphosphorilationandCKIs(CDK inhibitorproteins) • Theriseandfallofthecyclinlevels are themaineventsthatcontroltheactivityofCDKsduringthecellcycle. However, othermechanismshelptheactivityofCDKs in specificstagesofthecycle.

  13. InhibitorphosphorilationandCKIs(CDK inhibitorproteins) • Thephosphorilation in a pairofaminoacidsonthe top ofthekinases’ active site inhibitsthecyclin-cdkcomplex. • Cellsusually use CKIs to helpthem in the G1-S regulationactivity in thebeginningofthecellcycle. There are some typesofCKIssuch as P15,P16,P18 and P19.

  14. Retinoblastoma protein (Rb) • Important target of G1 CDKS • In mid- to late- G1, Rbisphosphorylatebycyclin D1- cdk4/6 andcyclin E-cdk2 complexes • Rb (hyperphosphorylated) is no longerrepressedby E2F • E2F bindswith DP • Activate genes required for S phaseprogression

  15. Cellcycle’sderegulationand cardiovascular diseases • Hypothesis: Onesignalwhichmaycontrolischemic neuronal deathistheinappropriateactivationofcellcycleregulatorsincludingcyclins, cyclindependentkinases (CDK) andendogenouscyclindependentkinasesinhibitors (CDKI). Aberrantactivationoftheseelementstriggers neuronal death

  16. Stroke • Occludedorrupturedofbloodvesselsand in some cases cardiacarrest. Neurons in theaffectedbrainregion are privedofoxigenand glucose. Ischemic neuronal deathisdeterminedbylocation, severityanddurationofinsult.

  17. CellcyclemachineryandStrokeIn vitro evidence

  18. CellcyclemachineryandStrokeIn vitro evidence J. Rasidian, G.O. Iyirhiaro, D.S. Park, Cellcyclemachineryandstroke, BBA – Molecular BasisofDisease (2006), doi: 10.1016 / j.bbadis.2006.11.009

  19. CellcyclemachineryandStrokeIn vitro evidence • Normal conditions: • Thelevelsofactivityofkeycellcycle are downregulated; • More activityofCKIs; • ThelevelsofhypophosphorylatedRbincreasesresulting in greaterE2F sequestration.

  20. CellcyclemachineryandStroke In vitro evidence Ischemicinjuryconditions: • LoseofCKIs example: CDK inhibitor p27 isreportedlossof CKI followingoxygen glucose deprivation (stroke) • Increase in Cyclins example: cyclin D1 proteinlevelsandactivationof Cdk2 afterstroke • Rbisphosphorylatedfollowinghypoxia/reoxygenation • Increase in E2F mRNAtranscription Activationofthecellcycle

  21. CellcyclemachineryandStroke Thisonlyshowedtheactivationofcellcyclecomponentsand does notadressstheissueofwhetherthissignalisrequired for death

  22. CellcyclemachineryandStroke J. Rasidian, G.O. Iyirhiaro, D.S. Park, Cellcyclemachineryandstroke, BBA – Molecular BasisofDisease (2006), doi: 10.1016 / j.bbadis.2006.11.009

  23. CellcyclemachineryandStroke • Proceeding 1:use drugsthatinactivatethecellcycle, such as CDK inhibitorslikeflavopiridol • Conclusion 1: the cortical neuronshavebeenprotected

  24. CellcyclemachineryandStroke • Proceeding 2: geneticmanipulationofcomponentsofthecellcycle • Conclusion 2: in micewithexpressingkinasedead cdk4 ornull for itsregulatorcyclin (D1) are resistent to hypoxiamediatedischemicdeath

  25. CellcyclemachineryandStroke • Proceeding 3: envisionofthecellcyclepathwaywith E2F null • Conclusion 3:cortical neuronsderivedfrom E2F nullmice are lesssusceptible to deathbyhypoxia Furthermore E2F deficiency improves therecoveryofneuronsfromlossofsynaptictransmission

  26. CellcyclemachineryandStroke Takentogether, these in vitro evidencestronglyimplicatethereactivationofcellcyclecomponents in ischemic neuronal death.

  27. Cellcycle role inatherosclerosis Theatheroscleroticplaqueisdue to anoverproliferationofendothelial, smoothmuscle, andinflammatorycellsandmacrophages Thedivisionofthesecellsisactivatedby a AllograftInflammatory Factor (AIF-1)

  28. Cellcycle role inatherosclerosis • AIF-1 isnotpresentin normal arteries, anditisproducedby VSMC whenthey are stimulated.Constitutiveexpression of AIF-1 results in a shorter cell cycle, and aberrant expression of cell cycle proteins. • AIF-1 actively participates in the upregulation of VSMC’s proliferation Thishappensbecause AIF-1, alongsidewithcalmodulin, shortensthe G1 andantecipatesthe S phase

  29. Cellcycle role inatherosclerosis • Thisisimportant to copewiththeinflammatory processes. Butifthishappensinordinarysituations, itmay cause a overproductionof VSM cells, obtructing crucial arteriesofthe cardiovascular system. AtheroscleroticRestenosis

  30. Bibliography • Alberts B., Bray D., Lewis J., M. Raff, Roberts K., & Watson J.D. (1994) Molecular Biology of the Cell, 3rd Ed. Garland Publishing, Inc. New York. Netgraphy • http://www.nature.com/scitable/topicpage/cdk-14046166 • http://atvb.ahajournals.org/content/21/9/1421.short • https://sites.google.com/site/kefalikinisi/home/fisiologia-humana-1/celula-e-celulas/ciclo-celular • http://scholar.google.pt/scholar?start=10&q=deregulation+in+cell+cycle+and+cardiovascular+diseases&hl=pt-PT&as_sdt=0 Articles •  J. Rasidian, G.O. Iyirhiaro, D.S. Park, Cellcyclemachineryandstroke, BBA – Molecular BasisofDisease (2006), doi: 10.1016 / j.bbadis.2006.11.009 • Michael V. Autieri, Christopher M. Carbone - Overexpression of Allograft Inflammatory Factor-1 Promotes Proliferation of Vascular Smooth Muscle Cells byCellCycleDeregulation(ArteriosclerThrombVasc Biol. 2001;21:1421-1426.)

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