Cell Bio Ch 18: The Cell-Division Cycle

Cell Bio Ch 18: The Cell-Division Cycle

1. Cell-Cycle Control System:

   • 3 Main Transition Points?
     • G1 to S Phase
       • Checks if environment is favorable for DNA Replication
         • S-Cdk
           • Cyclin A
         • G1/S-Cdk
           • Cyclin E
           • p27
             • inhibitory protein, its binding prevents Cdk from phosphorylating target proteins
         • G1-Cdk
           • Cyclin D
       • Cdk inhibitors
     • G2 to M Phase
       • Ensures DNA was accurately replicated in S phase and was not damaged
         • M -Cdk
           • Cyclin B
           • Wee1
             • Inhibitory protein kinase, immediately phosphorylates the M cyclin-Cdk complex
               • Cdc25
                 • activating protein phosphatase removes the phosphate so M-Cdk is active when it is needed in the cell cycle
       • Inhibits the phosphatase that activates M-Cdk
     • During mitosis
       • Ensures duplicated chromosomes are properly attached to mitotic spindle before they are pulled apart
       • Inhibits activation of APC (prevents degradation of M cyclin)
   • 2 "Types of Machinery" In cell Division
     • makes new parts of growing cell
   • Works by cyclically activating / inactivating proteins that are responsible for cell cycle functions; based on phosphorylation and dephosphorylation
     • Cyclin-dependent Protein Kinases (Cdks)
       • present throughout cell cycle but only activated at appropriate times
         • cyclins
           • proteins that must bind to Cdks for the kinases to become enzymatically active
           • concentration of these does vary throughout cell cycle
           • cyclin-cdk complex then triggers various cell-cycle events
           • cyclin-Cdk complex
             • Regulation of Cyclin-Cdk complex
               • Phosphorylation / Dephosphorylation
                 • contains an inhibitory phosphatase; must be dephosphorylated to be activated
               • Cdk inhibitor proteins
                 • Binding of these blocks the assembly of cyclin-cdk complexes
               • cyclin degradation
                 • Tags M-Cyclin or S-Cyclin with ubiquitin so the Cdk becomes in active as the cyclin is destroyed

2. M Phase

   • Mitosis
     • nucleus divides
     • chromosome condensation
       • condensins
         • proteins that help make mitotic chromosomes more compact
         • activated via phosphorylation by M-cdk
     • sister chromosomes held together immediately after replication in S phase
       • cohesins
     • mitotic spindle
       • made of microtubules, job is to separate the sister chromosomes and place one copy in each daughter cell that is forming
     • the period in which chromosomes are visible!
   • Cytokinesis
     • cell splits in two (cytoskeleton divides)
       • daughter cells flatten out (they had rounded up in M phase)
       • ER is also cut in two so both daughter cells receive some
     • contractile ring
       • made of actin and myosin filaments, pulls membrane inwards to divide the cell in two
     • starts in anaphase as the plasma membrane furrows perpendicular to long axis of mitotic spindle
       • this is due to proteins that signal to the cell cortex to start constructing the contractile ring
   • must accurately split up chromosomes so each daughter cell gets identical copy of genome
   • m-cdk
     • superstar of M-phase. Gets the duplicated chromosomes organized to split up and helps assemble the mitotic spindle which will be doing the pulling apart
     • once one M-cdk complex is activated, each can activate additional ones
     • shuts down Wee1 so more M-cdk can be made

3. Interphase

   • The period between M phases
   • S Phase
     • cell replicates DNA. Each nucleotide must be copied exactly once
     • prereplicative complex
       • origin recognition complex (ORC)
       • recruits Cdc6 protein
       • load DNA helicases for replication
     • S -Cdk
       • triggers S phase
       • phosphorylates Cdc6 to prevent double replication
   • G1 Phase
     • Cell growth, repair, & metabolic activity
     • Decides to hold in G1 or start S phase of another cell cycle- the starting point (cell usually continues after that). Cell enters S phase if stimulated by mitogens
     • start transition
     • Cdks are inactivated by destroying cyclins, not making new ones, and blocking activity of complexes. No cdks active in G1
     • mitogens
       • positive control
       • switch on pathways that stimulate synthesis of G1-cyclins, G1/S cyclins, other proteins involved in S phase
     • Retinoblastoma (Rb) Proteins
       • negative control
       • in the nucleus of all vertebrae cells
       • "Rb brake":attaches to transcription regulators. Represses transcription required for cell to go from G1 to S phase
         • G1-Cdks and G1/S-Cdks release the break by phosphorylating the Pb protein to release it
     • p53 protein
       • if DNA is damaged, activity goes up. Activstes transcription of p21
         • p21 protein
           • Cdk inhibitor protein, binds to G1/S-cdk and S-cdk to prevent them from letting cell go into S phase
           • gives cell time to repair DNA if it is damaged before it replicates in S phase
           • induces apoptosis if cell is damaged beyond repair
       • 50% of human cancers have mutated p53 protein, causing unrestrained replication of cells
     • longest phase of cell cycle!
   • G2 Phase
     • Cell prepares for M Phase, continues to grow
     • Cdc25
       • Protein phosphatase responsible for removing phosphates from M-cdk complexes to allow progression into M-phase
       • inhibited if DNA is damaged or not fully replicated
         • no Cdc25 = Cell is stuck in G2, can't move on to M phase

4. G0

   • specialized resting phase (temporary)

5. terminally differentiated cells

   • nerve cells, muscle cells
   • cell cycle control system = completely dismantled (cells permanently stop dividing), genes related to cyclins and Cdks shut down

6. phases of mitosis! etc.

   • before mitosis begins!
     • 1. DNA fully replicated
     • 2. Centrosome duplicated!
       • centrosome organizes the microtubules bruh
       • duplicates to form 2 poles of mitotic spindle
   • centrosome cycle!
     • centrosomes separate and each forms an aster
       • wild array of microtubules (crazy hair)
       • asters move to two moles of mitotic spindle
         • two centrosomes are now called spindle poles!
         • colchicine: drug that blocks addision of tubulin to microtubules, metaphase spindle sidappears
     • 1. Prophase
       • 2. Prometaphase
         • 3. Metaphase
           • 4. Anaphase
             • 5. Telophase
               • chromosomes align at poles of mitotic spindle
               • new nuclear envelopes assemble around each group of chromosomes to form two daughter nuclei
                 • condensed chromosomes decondense
               • cytokinesis
                 • contractile ring divides the cytoplasm in two
             • begins with breakage of cohesin linkages that help sister chromatids together
             • separase protease breaks the cohesin linkages but held inactive by securin
               • Anaphase Promoting Complex (APC) tags securing for destruction using ubiquitin
                 • activation of APC blocked if chromosomes unnatached; sister chromatids remain glued together, spindle assembly checkpt
             • anaphase a
               • kinetochore microtubules get shorter, chromosomes move towards spindle poles
             • anaphase b
               • poles are pushed apart via a sliding force and a pulling force furter pulles the poles apart towards the cell cortex
           • chromosomes align halfway between spindle poles
         • nuclear membrane breaks down as nuclear pore proteins and nuclear lamins are phosphorylated
         • chromosomes can attach to spindle via their kinetochores
       • mitotic spindle assembles
         • formed by stabilization of microtubules

7. Apoptosis!

   • programmed cell death (intracellular)
     • clean and neat, doesn't affect neighbors
     • caspases
       • procaspases
         • inactive precursors, wait for signals that induce apoptosis
       • initiator caspases
         • cleave and activate executioner caspases
       • executioner caspases
         • start a cascade of caspases- "release a killer army"
           • cascade is irreversible once it has begun, "all or nothing"
         • break down key proteins in the cell, such as breaking down nuclear lamina and allowing nucleases to break down DNA
       • Bcl2 family
         • proteins that regulare caspase activation- some promote it, some inhibit it.
           • Bax and Bak proteins
             • promote cell death
             • induce the release of cytochrome C from mitochondria into cytosol
               • cytochrome C activates initiator caspases
               • promotes assembly of apoptosome protein complex
                 • apoptosome recruits a protein cascade that starts a caspase cascade
           • Bcl2 protein
             • inhibits cell death
               • prevents Bax and Bak from releasing cytochrome C
   • cell death usually balances cell division in adult tissue that remains the same size
   • cell necrosis
     • cells that die of injury swell and burst (messy), triggers an inflammatory response in the cell
   • cell shrinks and condenses, cytoskeleton collapses, nuclear envelope disassembles, attracts phagocytic cells
     • macrophages
       • surround and "eat" the apoptotic cell via phagocytosis so the cell doesn't make a mess and explode everywhere
   • regulation of apoptosis
     • intracellular
       • Bcl2 family: such as in response to DNA damage
     • extracellular
       • death receptors
         • cell-surface receptor proteins
         • Fas
           • activated by membrane-bound Fas Ligand
             • Present on surface of killer lymphocytes (special immune cells)
               • induce apoptosis in other immune cells that are no longer wanted / needed
             • binding of Fas ligand triggers a caspase cascade
   • Extracellular signals that affect the cell cycle (excitatory)
     • survival factors
       • suppress apoptosis
       • makes sure cells only survive when and where they are needed- adjust # of developing nerve cells
         • limited amount of survival factors released while nerve cells are produced in excess
       • activates cell-surface receptors that turn on intracellular signaling pathways which suppress apoptosis
         • can activate transcription of the gene encoding Bcl2!
     • mitogens
       • stimulate cell division at G1 Checkpoint (Entry into S Phase)
     • growth factors
       • stimulate cell growth by promoting synthesis
         • bind to cell-surface receptors that activate intracellular signaling pathways which increase synthesis and decrease degradation of macromolecules
         • PDGF
           • Can act as both a mitogen and a growth factor
     • Extracellular signal proteins that inhibit the cell cycle-inhibit tissue growth
       • myostatin
         • normally inhibits growth and proliferation of skeletal muscle cells

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