1. C ELL D IVISION C YCLE Kanokporn Boonsirichai

2. T WO T YPES OF C ELL D IVISION Mitosis Chromosome number is preserved. Meiosis Chromosome number is reduced by half.

3. M ITOSIS

4. M EIOSIS Crossing over Meiosis does two things - 1) Meiosis takes a cell with two copies of every chromosome (diploid) and makes cells with a single copy of every chromosome (haploid). 2) Meiosis scrambles the specific forms of each gene that each sex cell (egg or sperm) receives.

5. Crossing over Independent assortment

6. C ONTROL OF CELL CYCLE Figure 18-1 Essential Cell Biology (© Garland Science 2010)

7. Prokaryote: Escherichia coli~ 20 minutes

8. Figure 18-2 Essential Cell Biology (© Garland Science 2010) P HASES OF THE C ELL C YCLE

9. C ELL C YCLE C ONTROL S YSTEM A timer/clock: when and how long A play list: ordering of event Preventions of repeats On/off switches Backup mechanisms Adaptibility/sensors

10. C ELL C YCLE C HECKPOINTS Cause the cell to become arrested at a specific point in the cell cycle, if previous events have not been completed Utilize negative signals

11. What do you think might be the nature of the cell cycle control system?

12. C YCLIN -C DK C OMPLEXES Cdk (cyclin-dependent kinase): cyclically activated protein kinase Cyclin: switches Cdk on and off Figure 18-5 Essential Cell Biology (© Garland Science 2010)

13. C YCLIN - C DK A CTIVITY AND C ELL C YCLE

14. F OUR CLASSES OF CYCLINS G1 cyclins promote the cell through “Start” or restriction point in late G1 G 1 /S-cyclins bind Cdks at the end of G1 and commit the cell to DNA replication S-cyclins bind Cdks during S phase and are required for initiation of DNA replication M-cyclins promote the events of mitosis wikipedia

15. M AJOR CYCLINS AND C DKS Cyclin- Cdk complex VertbrateBudding yeast CyclinCdkCyclinCdk G 1 -Cdkcyclin DCdk4, 6Cln3Cdk1 G 1 /S-Cdkcyclin ECdk2Cln1, 2Cdk1 S-Cdkcyclin ACdk2Cln5, 6Cdk1 M-Cdkcyclin BCdk1Cln1, 2, 3, 4 Cdk1

16. Figure 18-10 Essential Cell Biology (© Garland Science 2010)

17. A CTIVATION OF C DKS Binding to cyclins Phosphorylation by Cdk-activating kinase (CAK) near the entrance of the active site Figure 18-9 Essential Cell Biology (© Garland Science 2010)

18. I NHIBITION OF C DK ACTIVITY Binding of cyclin-Cdk complexes by Cdk inhibitor proteins (CKI) Proteolysis of cyclin

19. Figure 18-12 Essential Cell Biology (© Garland Science 2010) C ELL C YCLE C HECKPOINTS At G1 checkpoint, cell decides whether to commit to another cell cycle. At each checkpoint, cell may be arrested if conditions are not favorable.

20. T HE S P HASE Active S-Cdk Initiation of DNA replication Prevention of rereplication

21. I NITIATION OF DNA R EPLICATION

22. R EGULATION AT THE O RIGIN OF DNA R EPLICATION S-Cdk allows DNA replication to initiate.

23. Mcm Export from the nucleus S-Cdk M-Cdk Cdc6 Ubiquityl ation by SCF S-Cdk M-Cdk P REVENTION OF R E - REPLICATION

24. T HE M P HASE Chromosome separation Figure 18-17 Essential Cell Biology (© Garland Science 2010)

25. R OLES OF M-C DK IN M ITOSIS Induces the assembly of the mitotic spindle Ensures that replicated chromosomes are attached to the spindle Triggers chromosome condensation, nuclear envelope breakdown, actin rearrangement, reorganization of Golgi apparatus and ER

26. P OSITIVE F EEDBACK L OOP Positive feedback loop allows for commitment to a cell cycle event. Figure 18-18 Essential Cell Biology (© Garland Science 2010)

27. S PINDLE - ATTACHMENT CHECKPOINT Ensures that all chromosomes are properly attached to the mitotic spindle before sister- chromatid separation occurs Unattached kinetochores send out a negative signal that blocks activation of Cdc20-APC complex Binding of Mad2 to unattached kinetochore, leading to inhibition of Cdc20-APC and securin degradation

28. Exit from Mitosis Figure 18-29 Essential Cell Biology (© Garland Science 2010)

29. C REATION OF G1 PHASE Destruction of M-cyclin at the end of mitosis leads to: inactivation of Cdc20-APC activation of Hct1-APC activation of Sic1 CKI decrease in the transcription of M cyclin gene

30. T RANSITION THROUGH S TART Extracellular signals cause an accumulation of G 1 cyclin (not sensitive to Hct1-APC and Sic1) G 1 -Cdk stimulates transcription of G1/S cyclin gene G1/S-Cdk stimulates transcription of S-cyclin gene

31. C ONTROL OF S- PHASE INITIATION

32. C ELL G ROWTH AND C ELL C YCLE P ROGRESSIO N

33. M ONITORING OF C ELL C YCLE P ROGRESSION Cln3, the budding yeast G1 cyclin, is synthesized in parallel to cell growth Cells may inherit a fixed amount of inhibitor that binds Cln3

34. DNA DAMAGE CHECKPOINTS Checkpoint in late G 1 prevents entry into S phase Checkpoint in late G 2 prevents entry into mitosis

35. G1 CHECKPOINT DNA damage leads to the activation of p53, a gene regulatory protein p53 stimulates expression of many genes including a CKI called p21, which binds G 1 /S-Cdk and S-Cdk

36. G2 CHECKPOINT Damaged DNA sends signals to inactivate Cdc25. Figure 18-17 Essential Cell Biology (© Garland Science 2010) X X

37. C ONTROL OF THE C ELL C YCLE

38. P ROGRAMMED CELL DEATH

39. F UNCTION OF APOPTOSIS To eliminate damaged cells Is an essential part of development in multicellular organisms Balances cell division to regulate tissue/organ size

40. Necrotic cells Apoptotic cells

41. C ASPASE C ASCADE Caspase is a class of proteases Contain cysteine at their active site Cleave at specific aspartic acid residue

43. E XTRACELLULAR CONTROL OF CELL DIVISION

44. E XTRACELLULAR S IGNALS Mitogens: stimulates cell division by relieving intracellular negative control Growth factors: stimulates cell growth by promoting synthesis of proteins and other macromolecules and inhibiting their degradation Survival factors: promotes cell survival by suppressing apoptosis

45. PDGF: P LATELET - DERIVED GROWTH FACTOR Functions as a mitogen Secreted by platelet cells to stimulate cell division during wound healing Can act on multiple cell types: fibroblasts, neuroglial cells, smooth muscle cells

46. M ITOGEN SIGNALING PATHWAY ( THROUGH GTP ASE R AS AND MAP KINASES )

47. O VERACTIVE MITOGENIC SIGNAL RESULTS IN CELL CYCLE ARREST OR APOPTOSIS

48. R EPLICATIVE C ELL S ENESCENCE Fibroblasts from normal human tissues can only go through 25-50 population doubling when cultured in standard mitogenic medium

49. G ROWTH FACTOR SIGNALING PATHWAY PI 3-kinase phosphorylates inositol phospholipid in the membrane activating S6 kinase which activates components of translational machinery

50. N ERVE CELLS GROWTH AND APOPTOSIS Survial factors are produced in limited amount Nerve growth factor (NGF)

51. S URVIVAL FACTOR SIGNALING PATHWAY

52. A NCHORAGE - DEPENDENT CELL DIVISION Cells are growth over non-adhesive substratum with or without a patch of adhesive palladium, fed with 3 H-thymidine and autoradiographed.

53. Integrins (cell surface matrix receptors) interact with laminin and/or fibronectin (extracellular matrix molecules, leading to activation of FAK (focal adhesion kinase) and signaling pathways that promote cell survival, growth and division Actin is labeled in green and proteins with phosphotyrosines are labeled in red

54. E XTRACELLULAR NEGATIVE SIGNAL PROTEINS TGF-  signal proteins inhibit the proliferation of many cell types (blocking progression through G 1 or stimulating apoptosis) BMP (bone morphogenetic protein) triggers apoptosis of cells between developing digits of a mouse paw

55. E XTRACELLULAR NEGATIVE SIGNAL PROTEINS Myostatin inhibits proliferation of myoblasts that fuse to form muscle cells Mutations in myostatin gene can cause an increase in muscle cell size and number

56. C ONTROL OF BODY SIZE Through the control of total cell mass Salamanders of different ploidy levels are of the same body size But their cell size and cell number are different Kidney tubules hindbrain Haploid Tetraploid

57. Q UESTION Describe a mechanism by which Cdk is activated during the cell cycle.