1.  Regulation of Cell Number and Cancer Cells Special Limited Edition Packet Tuesday, November 10, 20151

2.  There are intracellular and extra cellular signals that control the cell cycle and apoptosis. Tuesday, November 10, 20152

3. Intracellular Controls  Intracellular controls may either be “negative” controls or “positive” controls.  Negative controls will stop either the cell cycle or apoptosis  Positive controls will promote either the cell cycle or apoptosis. Tuesday, November 10, 20153

4.  Cell Cycle Negative Intra Cellular Controls Tuesday, November 10, 20154

5. Negative Intracellular Control I  DNA is damaged during the S phase Tuesday, November 10, 20155

6. Negative Intracellular Control I  p53 is activated and produces p53 protein. Tuesday, November 10, 20156

7. Negative Intracellular Control I  p53 protein becomes a transcription factor for p21 gene.  p21 is activated. Tuesday, November 10, 20157

8. Negative Intracellular Control I  p21 inhibitor protein is produced.  This inhibitor protein is an inhibitor of cyclin dependent kinase complexes. (CDK complexes) Tuesday, November 10, 20158

9. Negative Intracellular Control I  p21 inhibitor protein inhibits CDK complex and stops the complex from activating E2F when it phosphorylates the Rb protein.  When E2F is inactive, the cell cycle stops. Tuesday, November 10, 20159

10.  Positive Intracellular Control The Cell Cycle Tuesday, November 10, 201510

11. Positive Intracellular Control I  When the damaged DNA is repaired (details to come in DNA replication packet), the previously mentioned process is reversed. Tuesday, November 10, 201511

12. Positive Intracellular Control II  p53 becomes deactivated and reduces the amount of p53 proteins. Tuesday, November 10, 201512

13. Positive Intracellular Control II  p21 gene is turned off/does not turn on.  CDK complex is activated/reactivated.  Cell cycle re-starts. Tuesday, November 10, 201513

14. Positive Intracellular Control III  Additionally, independent signals from within, or outside, the cell produce a cascade of protein kinases.  Initiates a phosphorylation cascade. Tuesday, November 10, 201514

15. Positive Intracellular Control III  Ultimately, the CDK complex is phosphorylated and becomes active. Tuesday, November 10, 201515

16. Positive Intracellular Control III  Activated CDK complex phosphoroylates the Rb protein.  Rb protein is turned off. Tuesday, November 10, 201516

17. Positive Intracellular Control III  E2F protein is released from the Rb protein.  E2F becomes active. Tuesday, November 10, 201517

18. Positive Intracellular Control III  E2F becomes a transcription factor and binds on the S-phase genes.  The S-phase proceeds forward. Tuesday, November 10, 201518

19.  Positive Intracellular Controls Apoptosis Tuesday, November 10, 201519

20. Introduction—Apoptosis  It has been known for several years that many forms of cellular damage trigger leakage of mitochondria.  Leakage of proteins from within the mitochondria.  This leakage indices the apoptotic response. Tuesday, November 10, 201520

21. Positive Intracellular Controls— Apoptosis  Cytochrome C, when leaked from the mitochondria, binds to an apoptotic protease activating factor (Apaf) to form the cytochrome c-Apaf complex. Tuesday, November 10, 201521

22. Positive Intracellular Controls— Apoptosis  The cytochrome c-Apaf complex activates the initiator capase.  Capases are proteins that behave as transcription factors and activate suicide genes.  They activate apoptosis. Tuesday, November 10, 201522

23.  Negative Intracellular Controls Apoptosis Tuesday, November 10, 201523

24. Introduction I  Once a capase becomes active, there is no way to stop apoptosis.  Therefore, mechanisms to prevent apoptosis from starting, under normal conditions, has been observed. Tuesday, November 10, 201524

25. Negative Intracellular Controls— Apoptosis  Bcl proteins block the release of cytochrome C from the mitochondria and has the ability to bind to Apaf and prevent the activation of the capases. Tuesday, November 10, 201525

26.  Positive Extracellular Controls The Cell Cycle Tuesday, November 10, 201526

27. Introduction  Cell division is promoted by the action of mitogens.  Polypeptide ligands released from paracrine sources within the immediate area.  Mitogens are also called growth factors. Tuesday, November 10, 201527

28. Mitogens  EGF (epidermal growth factor) activates RTK’s.  RTK = tyrosine receptor kinase.  RTK initiates an intracellular transduction pathway described previously.  CDK complex becomes phosphorylated and becomes active… Tuesday, November 10, 201528

29.  Negative Extracellular Controls The Cell Cycle Tuesday, November 10, 201529

30. Introduction  Certain secreted proteins are known to inhibit cells from dividing.  TGF- β  Transforming growth factor beta Tuesday, November 10, 201530

31. Negative Extracellular Controls I  TGF- β activates TGF- β receptor (a type of tyrosine kinase receptor). Tuesday, November 10, 201531

32. Negative Extracellular Controls I  SMAD proteins are phosphorylated.  Phosphorylation cascade. Tuesday, November 10, 201532

33. Negative Extracellular Controls I  CDK complex becomes phosphorylated.  Rb protein is turned on.  Rb protein binds to E2F…stopping the cell cycle. Tuesday, November 10, 201533

34.  Positive Extracellular Controls I Apoptosis Tuesday, November 10, 201534

35. Positive Extracellular Controls I Tuesday, November 10, 201535

36. Tuesday, November 10, 201536