2 Frequency of cell division Frequency of cell division varies by cell typeembryocell cycle < 20 minuteskin cellsdivide frequently throughout life12-24 hours cycleliver cellsretain ability to divide, but keep it in reservedivide once every year or twomature nerve cells & muscle cellsdo not divide at all after maturitypermanently in G0G2SG1Mmetaphaseprophaseanaphasetelophaseinterphase (G1, S, G2 phases)mitosis (M)cytokinesis (C)C
3 “Go-ahead” signals Protein signals that promote cell growth & division internal signals“promoting factors”external signals“growth factors”Primary mechanism of controlphosphorylationkinase enzymeseither activates or inactivates cell signalsWe still don’t fully understanding the regulation of the cell cycle. We only have “snapshots” of what happens in specific cases.
4 Spindle checkpoint G2 / M checkpoint M cytokinesis C G2 mitosis G1 S Chromosomes attached at metaphase plateReplication completedDNA integrityInactiveActiveActiveInactiveCdk / G2 cyclin (MPF)MAPCcytokinesisCG2mitosisG1SCdk / G1 cyclinInactiveMPF = Mitosis Promoting FactorAPC = Anaphase Promoting ComplexActiveG1 / S checkpointGrowth factorsNutritional state of cellSize of cell
6 External signals Growth factors coordination between cells protein signals released by body cells that stimulate other cells to dividedensity-dependent inhibitioncrowded cells stop dividingeach cell binds a bit of growth factornot enough activator left to trigger division in any one cellanchorage dependenceto divide cells must be attached to a substrate“touch sensor” receptors
7 Example of a Growth Factor Platelet Derived Growth Factor (PDGF)made by platelets in blood clotsbinding of PDGF to cell receptors stimulates cell division in connective tissueheal woundsErythropoietin (EPO): A hormone produced by the kidney that promotes the formation of red blood cells in the bone marrow. EPO is a glycoprotein (a protein with a sugar attached to it).The kidney cells that make EPO are specialized and are sensitive to low oxygen levels in the blood. These cells release EPO when the oxygen level is low in the kidney. EPO then stimulates the bone marrow to produce more red cells and thereby increase the oxygen-carrying capacity of the blood.EPO is the prime regulator of red blood cell production. Its major functions are to promote the differentiation and development of red blood cells and to initiate the production of hemoglobin, the molecule within red cells that transports oxygen.EPO has been much misused as a performance-enhancing drug (“blood doping”) in endurance athletes including some cyclists (in the Tour de France), long-distance runners, speed skaters, and Nordic (cross-country) skiers. When misused in such situations, EPO is thought to be especially dangerous (perhaps because dehydration can further increase the viscosity of the blood, increasing the risk for heart attacks and strokes. EPO has been banned by the Tour de France, the Olympics, and other sports organizations.
8 Growth Factors and Cancer Growth factors can create cancersproto-oncogenesnormally activates cell divisiongrowth factor genesbecome oncogenes (cancer-causing) when mutatedif switched “ON” can cause cancerexample: RAS (activates cyclins)tumor-suppressor genesnormally inhibits cell divisionif switched “OFF” can cause cancerexample: p53
9 Cancer & Cell GrowthCancer is essentially a failure of cell division controlunrestrained, uncontrolled cell growthWhat control is lost?lose checkpoint stopsgene p53 plays a key role in G1/S restriction pointp53 protein halts cell division if it detects damaged DNAoptions:stimulates repair enzymes to fix DNAforces cell into G0 resting stagekeeps cell in G1 arrestcauses apoptosis of damaged cellALL cancers have to shut down p53 activityp53 discovered at Stony Brook by Dr. Arnold Levine
10 p53 — master regulator gene NORMAL p53p53 allows cellswith repairedDNA to divide.p53proteinDNA repair enzymep53proteinStep 1Step 2Step 3DNA damage is causedby heat, radiation, orchemicals.Cell division stops, and p53 triggers enzymes to repair damaged region.p53 triggers the destruction of cells damaged beyond repair.ABNORMAL p53abnormalp53 proteincancercellStep 1Step 2DNA damage iscaused by heat,radiation, orchemicals.The p53 protein fails to stopcell division and repair DNA.Cell divides without repair todamaged DNA.Step 3Damaged cells continue to divide.If other damage accumulates, thecell can turn cancerous.
11 Development of CancerCancer develops only after a cell experiences ~6 key mutations (“hits”)unlimited growthturn on growth promoter genesignore checkpointsturn off tumor suppressor genes (p53)escape apoptosisturn off suicide genesimmortality = unlimited divisionsturn on chromosome maintenance genespromotes blood vessel growthturn on blood vessel growth genesovercome anchor & density dependenceturn off touch-sensor gene
12 What causes these “hits”? Mutations in cells can be triggered byUV radiationchemical exposureradiation exposureheatcigarette smokepollutionagegenetics
13 Tumors Mass of abnormal cells Benign tumor Malignant tumor abnormal cells remain at original site as a lumpp53 has halted cell divisionsmost do not cause serious problems & can be removed by surgeryMalignant tumorcells leave original sitelose attachment to nearby cellscarried by blood & lymph system to other tissuesstart more tumors = metastasisimpair functions of organs throughout body