Regulation of the Cell Cycle

1. Regulation of the Cell Cycle

2. Molecular Control System • Normal growth, development and maintenance depend on the timing and rate of mitosis • Cell-cycle control system consists of a set of checkpoints (G1, G2, and M phases of the cell cycle)

3. Checkpoints integrate a variety of internal (intracellular) and external (extracellular) information • For many cells, the G1 checkpoint is the “restriction point” • A go-ahead signal indicates that the cell will complete the cycle and divide • In the absence of a go-ahead signal, the cell may exit the cell cycle and remain in the non-dividing state called G0 phase • Many human cells are in the G0 phase until they die—muscle and nerve cells

4. External Factors that can Influence Cell Division • Chemical factors- • Lack of nutrients inhibit cell division • Presence of specific growth factors are needed for cell division • Platelet-derived Growth Factor (PDGF) is required for division of fibroblasts used in healing • Receptors on plasma membrane bind PDGF and trigger pathway to signal cell division

5. External Signals • Growth factors stimulate cell division

6. Figure 12.15 The effect of a growth factor on cell division

7. Figure12.15x Fibroblast growth

8. Physical factors- • Density-dependent inhibition • Cell division limited by quantities of nutrients and growth regulators • Anchorage-dependent inhibition • Cells must attach to substratum (surface) • Anchorage is signaled to cell-cycle control system by linkage between membrane proteins and elements of cytoskeleton

9. Figure 12.16 Density-dependent inhibition of cell division

10. Sequence of cell cycle events are synchronized by rhythmic changes in activity of certain protein kinases—enzymes that catalyze the transfer of a phosphate group from ATP to a target protein (phosphorylation) Phosphorylation causes change in shape that activates/inactivates target protein which affect the progression through cell cycle G2 Checkpoint

11. Changes in kinase activity regulated by regulatory proteins • The protein kinase, cyclin-dependent kinase (Cdks) are regulated by concentration of cyclin present

12. Cdk = Cyclin-dependent kinases -constant conc. in a growing cell Cyclins-activates kinases -accumulates in G2 MPF = maturation promoting factor -triggers M phase to start by phosphorylating a variety of proteins Example: proteins that degrade nuclear envelope -triggers own break down

13. Internal Signals • Anaphase does not begin until all chromosomes are attached to spindle at metaphase plate • Proteins at kinetochore signal pathway to keep Anaphase Promoting Complex (APC) inactive • When active the APC contains proteolytic enzymes which break down cyclin and thus initiates separation of sister chromatids during Anaphase

14. Cancer Cells have Escaped Cell-cycle Control Cancer cells do not respond normally to the body’s control mechanisms and divide excessively • Density-independent—make their own growth factors and continue to divide uncontrolled (“immortal”) • Anchorage-independent

15. Abnormal cells that escape cell-cycle control are products of mutated or transformed normal cells • May proliferate to form a tumor—an unregulated growing mass of cells within normal tissue • Benign tumor—if cells remain at the original site • Malignant tumor—if mass impairs normal function of one or more organs of the body • Excessive proliferation • Cells with unusual number of chromosomes • Aberrant metabolism • Detaches and migrates through body (metastasis)

16. Figure 12.17 The growth and metastasis of a malignant breast tumor

17. Figure 12-17x1 Breast cancer cell

18. Figure 12-17x2 Mammogram: normal (left) and cancerous (right)