The cell cycle, basic concepts
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The document provides an overview of the cell cycle, including its phases (M, G1, S, G2, G0), historical perspectives on its discovery, and key mechanisms regulating progression through the cycle. Regulation involves cyclins and cyclin-dependent kinases (CDKs), restriction points, the tumor suppressor protein p53, and CDK inhibitors like p21 and p16. Precise control of the cell cycle through these mechanisms ensures genetic information is accurately replicated and transmitted between daughter cells.
The cell cycle, basic concepts
- 1. JG NEL DEPT OF HAEMATOLOGY AND CELL BIOLOGY UFS SEPTEMBER 2008 The Cell Cycle, basic concepts
- 2. Lecture outline Historical perspective Phases of the cell cycle Regulation of the cycle The importance of the cycle
- 3. Introduction The cell is the basic structural and functional unit of all living organisms. Understanding how the cell cycle operates, and is controlled, is therefore an important problem in biology with implications for medicine
- 4. The cell cycle Universal process by which cells reproduce Underlies the growth and development of all living organisms –central to their heredity and evolution Results in Duplication Transmission of genetic information The precision with which the cell cycle is executed ensures survival of all living organisms
- 5. Historical perspective What we know today is the result of work done over the past +/- 150 years Nägeli(1844)+Remak(1852) -described the division of plant and animal cells Study of the cell cycle -began with the discovery of cell division
- 6. Phases of the cell cycle
- 7. Phases of the cell Cycle M phase Karyokinesis Cell’s chromosomes divided between two daughter cells Cytokinesis Cytoplasm divides –forming distinct cells G1 phase Between M phase and the beginning of DNA synthesis Cellular biosynthetic activities resume at a high rate Marked by the synthesis of various enzymes required in S phase
- 8. Phases of the cell Cycle S phase Starts when DNA synthesis commences Complete when all the chromosomes have been replicated Rates of RNA transcription and prot synth low during this phase -with the exception of histone production
- 9. Phases of the cell Cycle G2 Lasts until the cell enters mitosis Significant protein synthesis occurs –mainly involving the production of microtubules Inhibition of prot synth prevents cell from entering mitosis G0 Quiescent and senescent cells
- 11. Cell cycle regulation: Ensures the orderly progression of events so that the nuclear cycle is coordinated with cell growth and physical separation. Replication must occur once per cell cycle and precede chromosome segregation; segregation must be complete before cytokinesis.
- 12. Regulation of the cell cycle
- 13. 2001 Nobel prize in Physiology or Medicine
- 14. 2001 Nobel prize in Physiology or Medicine Leland Hartwell 60s Budding yeasts, identified specific mutants that blocked specific stages of the cell cycle Cell division cycle genes “start” gene in yeasts –CDC28 Checkpoints Paul Nurse 70s Isolated fission yeast mutants that could speed up the cell cycle CDK- cdc2, CDK-1 1987 discovers the human “start” gene Tim Hunt Discovered “cyclins”
- 15. Regulation of the cell cycle Crucial to the cell Involves the detection and repair of genetic damage Provision of various checks to prevent uncontrolled cell division Molecular events that control cell cycle –ordered and directional
- 16. Regulation of the cell cycle Role players: Cyclins + Cyclin-dependent kinases Restriction points P53 CDK inhibitors
- 17. Regulation of the cell cycle:CDKs
- 18. CDK-2
- 19. Regulation of the cell cycle:CDKs Exert their effects on cell-cycle events by phosphorylating a large number of proteins in the cell Two lobed structure Structure modified so that the active site of the CDK is blocked in the absence of cyclin
- 20. Regulation of the cell cycle: Cyclins and CDKs Cyclins -regulatory subunits CDKs -catalytic subunits Cyclins have no catalytic activity on their own Cyclins with their bound and activated CDK functions during distinct stages of the cell cycle Activated heterodimer
- 21. Regulation of the cell cycle:Cyclins Periodicity of Cyclins ensure well-delineated transitions between cell cycle stages Degradation by ubiquination and proteasomal degradation Details of conjugation to ubiquitins differ G1 cyclins -by SCF complex Mitotic cyclins -by APC
- 22. Regulation of the cell cycle: Restriction points
- 23. Regulation of the cell cycle: Restriction points Cell cycle proceeds by a defined sequence of events Later events depend on completion of earlier events Regulation necessary to ensure complete and accurate replication of genome Checkpoints set at various stages during the cell cycle Latter 1/3 of G1 In S phase G2/M Spindle checkpoint
- 24. Regulation of the cell cycle: Restriction points Checkpoints prevent cell cycle progression -allowing : Verification of necesary phase processes Repair of DNA damage
- 25. The location of checkpoints in the cell cycle
- 26. P53 protein
- 27. Regulation of the cell cycle: P53 Monitors the integrity of the genome In the presence of genomic damage –interrupts cycling to allow time for genomic repair Levels in normal dividing cells – low/undetectable Negatively regulated by MDM2
- 28. Regulation of the cell cycle: P53 MDM2 Negatively regulates p53 Functions at two sites Level of gene –down regulates p53 transcription Binds to P53 protein –inhibiting activity, mediating export from the nucleus, ubiquination and proteasomal degradation
- 29. Regulation of the cell cycle: P53 In presence of DNA damage P53 binds to sequence specific DNA site –inducing increased P53 protein synthesis Phosphorylation of p53 Activates the protein Renders the protein resistant to binding and inactivation by MDM2 – resulting in doubling of the half life of P53 and increasing activity of the protein Mechanism of P53 action Interrupts cell cycle by inhibition of Rb phosphorylation If damage too extensive for repair induces the expression of Bax
- 30. Regulation of the cell cycle: P53 Interrupts cell cycle by Transcriptional upregulation of P21, preventing phosphorylation of Rb by active inhibitiob of CDK 4,6,2
- 31. Regulation of the cell cycle: P53
- 32. The Rb protein
- 33. Regulation of the cell cycle: Rb proteins Pocket proteins Sequester E2F transcription proteins Release of E2F dependant upon the phosphorylation state of Rb protein Unphosphorylated/hypophosphorylated tightly binds E2F Phosphorylation By CDK4/6 E2F dissiociates from Rb –free to transcribe responder genes Cyclin E –required for progression through restriction point
- 34. Regulation of the cell cycle: Rb proteins Hypophosphorylated Rb guards restriction point – preventing cell cycle progression
- 35. Regulation of the cell cycle: CDK inhibitors Two families involved in cell cycle regulation Cip/Kip P27 +p21 Functions at several sites in the cell cycle Targets –CDK 4,6,2 INK4a P16INK4a Inhibits CDK4/6 P19ARF Binds to MDM2 and blocks P53 degradation Actions of CKI inhibits Rb phosphorylation and subsequently keeps the cell in G1
- 36. The cell cycle
- 37. The importance of the cell cycle Dynamic field Study of the cell cycle is providing insights into physiology and pathophysiology After 150 years of study , there is still a lot of things to learn, understand and prove.