Control of cell cycle by kinas

这是一篇关于Control of cell cycle by kinas的思维导图，主要内容有4 Stages of eukaryotic cell cycle、Levels of Cyclin-Dependent Protein Kinases Oscillate、The extracellular talk with cell cycles等。

Control of cell cycle by kinases

• 4 Stages of eukaryotic cell cycle
  • Diagram
  • S phase(synthesis phase)
    • DNA is replicated to produce copies
  • G2 phase(Gap)
    • new proteins are sythesized and the cell approximately double in size.
  • M phase(Mitosis)
    • The maternal nuclear envolope breaks down.
    • Paired chromosomes are pulled to the opposite poles of the cell.
    • each set of daughter chromosomes is surrounded by a newly formed nuclear envolope.
    • Cytokinesis pinches the cell in half, producing two daughter cells.
  • G1 phase
    • 2 selections
      • continous through another division
        • go to S phase
      • entering G0 phase(A quiescent phase)
        • last hours
          • days
          • entire life time of the cell
        • When cells leave G0, they re enter the division cycle through G1 phase
        • Differentiated cells aquire their specialized function and forms in G0 phase
          • like hepatocytes or adipocytes
  • Length of G1 is cell type dependend
    • In embryonic or rapidly proliferating tissue, each daughter cell divides again, but only after a waiting period (G1).
    • In cultured animal cells, the entire process takes about 24 hours.
• Levels of Cyclin-Dependent Protein Kinases Oscillate
  • Their activities change in response to cell signals
  • Behaviours of those kinases
    • They phosphorylate specific proteins at precisely timed intervals.
  • Structures of those kinases
    • Heterodimers
      • Regulatory subunit: cyclin
        • 10 different cyclins exist for animal cells.
          • Designate A,B,C and so forth
      • catalytic subunit: cyclin-dependent protein kinases (CDK)
        • At least 8 CDKs exist
          • CDK1-CDK8
          • Plants also use a family of CDKs to regulate their cell division in root and shoot meristems, the principal tissues in which division occurs
        • When cyclin binds, the catalytic site opens up (by moving away the T loop), a residue essential to catalysis (Glu 51) becomes accessible.
          • The activity of the catalytic subunit increases 10,000-fold.
        • In a population of cells undergoing synchronous division, some CDK activities show striking oscillations.
          • Those oscillations are the result of four mechanisms for regulating CDK activity
            • The number of different cyclins and kinases and their combinations are species specific
              • But the basic mechanism has been conserved through evolution
            • 1. Phosphorylation of dephosphorylation of the CDK.
              • on 2 critical residues of the protein
                • Phosphorylation of Tyr15 near the amino terminus inactivates CDK2.
                  • The P-Tyr residue is in the ATP-binding site of the kinase.
                    • The negatively charged phosphate group blocks the entry of ATP.
                  • A specific phosphatase dephosphorylates this P-Tyr residue, permitting the binding of ATP
                    • PTPase
                      • When presence of single-strand breaks in DNA, the cell needs to be arrested in G2
                      • A specific protein kinase called Rad3(in yeast) is activated by single-strand breaks, it triggers a cascade leading to the inactivation of the PTPase that dephosphorylates Tyr15 of CDK.
                      • The CDK remains inactivated, and the cell is arrested in G2, the cell cannot divide until the DNA is repaired and the effects of the cascade are reversed.
                • Phosphorylation of Thr160 in the "T loop" of CDK, activates the CDK
                  • Catalyzed by the CDK activating kinase
                  • Forces the T loop out of the substrate-binding cleft
                    • Permitting substrate binding and catalytic activity
            • 2. Controlled degredation of the cyclin subunit.
              • Highly specific and precise timed Proteolytic breakdown
                • G2-M checkpoint, progress to mitosis
                  • requires first the activation then the destruction of cyclins A and B
                    • Cyclin A and B contain destruction box, which near their N-terminus
                      • "Box"?
                        • The box indicates short consensus sequence of nucleotides or aminoacids
                          • Do infer specific functional information
                          • No structural informations
                      • -Arg-Thr-Ala-Leu-Gly-Asp-Iie-Gly-Asn-
                      • The sequence target the cyclins to degredation
                        • DBRP(destruction box recognizing protein)
                          • it recognize the distruction box and bing the cyclin together with ubiquitin, Cyclin and activated ubiquitin are covalently joined by the enzyme ubiquitin ligase.
                            • This initiates the process of cyclin degredation
                          • Several more ubiquitin molecules are then appended, providing the signal for proteosome to degrade cyclin.
                    • A feed back loop controls the timing of cyclin breakdown
                      • picture
                      • Increased CDK activity activates cyclin proteolysis
                        • activated CDK by cyclin will associates and activates DBRP, and promote proteolisis of CDK.
                          • The activity of DBRP also drops slowly after the CDK is distroyed
                            • beacuse the DBRP phosphatase constantly dephosphoralates and inactivates DBRP
                  • It activates the catalytic subunit of the M-phase CDK.
            • 3. Periodic synthesis of CDKs and cyclins
              • e.x. cyclin D, cyclin E, CDK2, and CDK4 are synthesized only when a specific transcription factor, E2F, is present in the nucleus to activate transcription of their genes.
                • picture
                • The synthesis of E2F is regulated by growth factors and cytokines
                  • Developmental signal that induces cell division
                  • Those are essential compounds for mammalian cells to divide in cell culture
                  • They also induce the synthesis of specific nuclear transcription factors essential to the production of the enzymes of DNA synthesis.
                  • Growth factors trigger phosphorylation of nuclear proteins Jun and Fos.
                    • They are transcription factors that promote the synthesis of a variety of gene products
                      • Cyclins
                      • CDKs
                      • E2F
                        • controls production of several enzymes essential for the synthesis of deoxynucleotides and DNA, enabling cells to enter S phase.
            • 4. The action of specific CDK-inhibiting proteins.
              • Specific protein inhibitors bind to and inactivate specific CDKs.
                • ex. P21
        • In general, active CDKs enable a cell to enter a stage of cell division.
  • Function of those kinases
    • The list of target proteins that CDKs are known to be act upon continous to grow, and much remains to be learned
      • CDK phosphorylate lamin in nuclear envelope, the phosphorylation depolarizes the lamin and cause the nucleus to break down
      • CDK phosphorylates actin and myocin, then they pinches a dividing cell into two equal parts during cytokinesis(ATP-driven contractile machinary)
        • After division, CDK phosphorylates a small regulatory subunit of myosin, causing dissociation of myosin from actin filaments and inactivating the contractile machinery.
        • Subsequent dephosphorylation allows reassembly of the contractile apparatus for the next round of cytokenisis.
      • CDK phosphorylates pRB(retinoblastoma protein)
        • When DNA damage is detected, this protein participates in a mechanism that arrests cell division in G1.
          • ATM and ATR are protein kinases, they phosphorylate and activate p53
        • it functions in most cell types, and regulates cell division in response to variety of stimuli.
• The extracellular talk with cell cycles
• When Eukaryotic cells need to divide
  • All tissues divide during embryonic growth and later development.
  • In the adult organism most tissues become quiesent.
• combination
  • They act in various combinations at specific points in the cell cycle.