Regulation of Cell Division AP Biology 2008 2009

Regulation of Cell Division AP Biology 2008 -2009

Coordination of cell division § A multicellular organism needs to coordinate cell division across different tissues & organs u critical for normal growth, development & maintenance § coordinate timing of cell division § coordinate rates of cell division § not all cells can have the same cell cycle AP Biology

Frequency of cell division § Frequency of cell division varies by cell type u embryo § cell cycle < 20 minute u skin cells § divide frequently throughout life § 12 -24 hours cycle u liver cells § retain ability to divide, but keep it in reserve M metaphase anaphase § divide once every year or two u prophase mature nerve cells & muscle cells G 2 § do not divide at all after maturity § permanently in G 0 S AP Biology telophase C interphase (G 1, S, G 2 phases) mitosis (M) cytokinesis (C) G 1

Checkpoint control system § Checkpoints cell cycle controlled by STOP & GO chemical signals at critical points u signals indicate if key cellular processes have been completed correctly u AP Biology

Checkpoint control system § 3 major checkpoints: u G 1 Checkpoint* § can DNA synthesis begin? u G 2 Checkpoint § has DNA synthesis been completed correctly? § commitment to mitosis u M Checkpoint § are all chromosomes attached to spindle? § can sister chromatids separate correctly? AP Biology

G 1/S checkpoint § G 1/S checkpoint is most critical u primary decision point § “Restriction point” u if cell receives “GO” signal, it divides § internal signals: cell growth (size), cell nutrition § external signals: “growth factors” u if cell does not receive signal, it exits cycle & switches to G 0 phase § non-dividing, working state AP Biology

G 0 phase § G 0 phase non-dividing, differentiated state u most human cells in G 0 phase u AP Biology § liver cells § in G 0, but can be “called back” to cell cycle by external cues § nerve & muscle cells § highly specialized § arrested in G 0 & can never divide

Activation of cell division § How do cells know when to divide? u cell communication signals § chemical signals in cytoplasm give cue § signals usually mean proteins w activators w inhibitors AP Biology experimental evidence: Can you explain this?

Cyclins and Cyclin-Dependent Kinases § Two types of regulatory proteins are involved in cell cycle control: cyclins and cyclin-dependent kinases (Cdks) § The activity of cyclins and Cdks fluctuates during the cell cycle § MPF (maturation-promoting factor) is a cyclin-Cdk complex that triggers a cell’s passage past the G 2 checkpoint into the M phase AP Biology

Fig. 12 -17 b G S Cdk M Degraded cyclin G 2 checkpoint Cyclin is degraded MPF (b) Molecular AP Biology G 2 Cdk Cyclin mechanisms that help regulate the cell cycle Cyclin accumulation 1 1. Cyclin produced in late S phase and continues through G 2. - Cyclin accumulates.

G Degraded cyclin 2. Cyclin combines with Cdk, producing MPF. When enough MPFMaccumulates, G 2 the cell begins mitosis. G 2 checkpoint Cyclin is degraded MPF (b) Molecular AP Biology Cdk Cyclin mechanisms that help regulate the cell cycle Cyclin accumulation Cdk S 1 Fig. 12 -17 b

G Cdk M Degraded cyclin G 2 checkpoint Cyclin is degraded MPF (b) Molecular AP Biology G 2 Cdk Cyclin mechanisms that help regulate the cell cycle Cyclin accumulation 3. MPF activity peaks during mitosis S 1 Fig. 12 -17 b

G M Degraded cyclin G 2 checkpoint Cyclin is degraded MPF (b) Molecular AP Biology G 2 Cdk Cyclin mechanisms that help regulate the cell cycle Cyclin accumulation Cdk 4. During Anaphase, cyclin degrades and terminates M phase. The cell enters the G 1 phase. S 1 Fig. 12 -17 b

Fig. 12 -17 b G S Cdk M Degraded cyclin G 2 checkpoint Cyclin is degraded MPF (b) Molecular AP Biology G 2 Cdk Cyclin mechanisms that help regulate the cell cycle Cyclin accumulation 1 5. During G 1, the degradation of Cyclin continues and Cdk of MPF is recycled.

Fig. 12 -17 a M G 1 S G 2 M G 1 MPF activity Cyclin concentration Time (a) Fluctuation of MPF activity and cyclin concentration during the cell cycle AP Biology

Growth Factors and Cancer § Growth factors can create cancers u Growth promoter genes § normally activates cell division w growth factor genes w become oncogenes (cancer-causing) when mutated § if switched “ON” can cause cancer § example: RAS (activates cyclins) u Regulator gene § normally inhibits cell division § if switched “OFF” can cause cancer § example: p 53 AP Biology

Cancer & Cell Growth § Cancer is essentially a failure of cell division control u unrestrained, uncontrolled cell growth § What control is lost? u u lose checkpoint stops gene p 53 plays a key role in G 1/S restriction point § p 53 protein halts cell division if it detects damaged DNA p 53 is the w options: Cell Cycle Enforcer n n stimulates repair enzymes to fix DNA forces cell into G 0 resting stage keeps cell in G 1 arrest causes apoptosis of damaged cell § ALL cancers have to shut down p 53 activity AP Biology p 53 discovered at Stony Brook by Dr. Arnold Levine

p 53 — master regulator gene NORMAL p 53 allows cells with repaired DNA to divide. p 53 protein DNA repair enzyme p 53 protein Step 1 Step 2 Step 3 DNA damage is caused by heat, radiation, or chemicals. Cell division stops, and p 53 triggers enzymes to repair damaged region. p 53 triggers the destruction of cells damaged beyond repair. ABNORMAL p 53 abnormal p 53 protein Step 1 DNA damage is caused by heat, radiation, or AP chemicals. Biology cancer cell Step 2 The p 53 protein fails to stop cell division and repair DNA. Cell divides without repair to damaged DNA. Step 3 Damaged cells continue to divide. If other damage accumulates, the cell can turn cancerous.

Development of Cancer § Cancer develops only after a cell experiences ~6 key mutations (“hits”) u unlimited growth § turn on growth promoter genes u ignore checkpoints § turn off tumor suppressor genes (p 53) u escape apoptosis § turn off suicide genes u immortality = unlimited divisions § turn on chromosome maintenance genes u It’s like an out of control car with many systems failing! promotes blood vessel growth § turn on blood vessel growth genes u AP Biology overcome anchor & density dependence § turn off touch-sensor gene

What causes these “hits”? § Mutations in cells can be triggered by u u AP Biology UV radiation chemical exposure radiation exposure heat u u cigarette smoke pollution age genetics

Tumors § Mass of abnormal cells u Benign Tumor § abnormal cells remain at original site as a lump w p 53 has halted cell divisions § most do not cause serious problems & can be removed by surgery u Malignant Tumor § cells leave original site w lose attachment to nearby cells w carried by blood & lymph system to other tissues w start more tumors = metastasis § impair functions of organs throughout body AP Biology

Traditional treatments for cancers § Treatments target rapidly dividing cells u high-energy radiation § kills rapidly dividing cells u chemotherapy § stop DNA replication § stop mitosis & cytokinesis § stop blood vessel growth AP Biology

New “miracle drugs” § Drugs targeting proteins (enzymes) found only in cancer cells u Gleevec § treatment for adult leukemia (CML) & stomach cancer (GIST) § 1 st successful drug targeting only cancer cells without Gleevec Novartes AP Biology with Gleevec

Any Questions? ? AP Biology 2008 -2009