More for Chapter 19

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More for Chapter 19
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Checkpoint Spindle Assembly

• APC is inhibited when microtubules are not
  attached to the kinetochore
• Mad and Bub bind and block Cdc20 from binding
  which activates APC
• When spindle is attached, the Mad and Bud no
  longer bind Cdc20 which now can bind to APC and
  activate it

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DNA Replication Checkpoints

• Final step in removing the 2nd inhibiting PO4
  from mitotic Cdk-cyclin complex is halted until
  DNA is repaired
• Build up of p53 results in 2 possible outcomes
• cell cycle arrest until repair is finished
• cell death - apoptosis

4
DNA Damage Checkpoint

• DNA damage triggers ATM protein synthesis that
  prevents the degradation of p53 by Mdm2
• p53 is phosphorylated twice and then can become a
  transcription factor

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p53-(PO4)2 Activity

• In cases of minor DNA damage p53 will initiate
  expression of p21 that will halt cell cycle and
  also trigger the enzymes necessary for DNA repair
• In cases of severe DNA damage p53 initiates
  Puma expression that will cause apoptosis by
  blocking inhibitor Bcl-2

6
Cell Cycle Regulation Machine - Clock

• Clock is the cyclin concentration
• Adjust by feedback kinases and phosphatases

7
Growth Factor Roles

• Yeast and bacteria regulate growth based on the
  presence of available nutrients
• Multi-celled organisms need to use stimulating
  and inhibiting growth factors otherwise may get
  unrestricted growth in cells based on available
  nutrients
• GF are mitogen activators push into S phase

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Ras Pathway

• Stimulatory
• GF binds
• Receptor cluster, dimerize and PO4
• Tyr-PO4 is binding site that will activate Ras
• Ras PO4 Raf that put PO4 on Ser/Thr on MEK that
  PO4 MAPK
• MAPK moves to nucleus and activates transcription
  factors
• Jun, Ets family turn on early genes that make
  additional transcription factors
• Myc, Fos, Jun turn on delayed genes such as E2F
• Delayed genes are for Cdk or cyclins

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PI3K-Akt Pathway

• Activate PI3-kinase that adds a PO4 to PIP2
  PIP3
• Recruits kinase to plasma membrane and activate
  Akt that will prevent cell cycle arrest and cell
  death
• Promotes cell survival
• PTEN is a phosphatase that will dephosphorylate
  PIP3 and inactivate the Akt pathway
• mutation in PTEN in seen in about 50 of prostate
  cancers and 35 of uterine cancers

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Inhibitory Pathways

• Transforming growth factor ß - TGF ß can both
  stimulate and inhibit the cell cycle
• When inhibitory binds the PO4-Smads in the
  nucleus and regulate gene expression
• increase the expression of p15 and p21 which are
  Cdk inhibitors