Cell Cycle Regulation PDF

Cell Biology Presented by Dr Ghada Khawaja Regulation of Cell Cycle Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Coordination of cell division  A multicellular org...

Cell Biology Presented by Dr Ghada Khawaja Regulation of Cell Cycle Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Coordination of cell division  A multicellular organism needs to coordinate cell division across different tissues & organs  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  embryo  cell cycle < 20 minute  skin cells  divide frequently throughout life  12-24 hours cycle  liver cells  retain ability to divide, but keep it in reserve M  divide once every year or two metaphase anaphase prophase telophase  mature nerve cells & muscle cells G2 C  do not divide at all after maturity  permanently in G0 interphase (G1, S, G2 phases) mitosis (M) cytokinesis (C) G1 S AP Biology There’s no turning back, now! Overview of Cell Cycle Control  Two irreversible points in cell cycle  replication of genetic material  separation of sister chromatids  Checkpoints  process is assessed & possibly halted sister chromatids centromere   single-stranded AP Biology double-stranded chromosomes chromosomes  Checkpoint control system  Checkpoints  cell cycle controlled by STOP & GO chemical signals at critical points  signals indicate if key cellular processes have been completed correctly AP Biology Checkpoint control system  3 major checkpoints:  G1/S  can DNA synthesis begin?  G2/M  has DNA synthesis been completed correctly?  commitment to mitosis  spindle checkpoint  are all chromosomes attached to spindle?  can sister chromatids separate correctly? AP Biology  G1/S checkpoint  G1/S checkpoint is most critical  primary decision point  “restriction point”  if cell receives “GO” signal, it divides  internal signals: cell growth (size), cell nutrition  external signals: “growth factors”  if cell does not receive signal, it exits cycle & switches to G0 phase  non-dividing, working state AP Biology G0 phase  G0 phase  non-dividing, differentiated state  most human cells in G0 phase M  liver cells Mitosis  in G0, but can be G2 Gap 2 “called back” to cell G1 Gap 1 cycle by external cues  nerve & muscle cells G0 S Resting  highly specialized Synthesis  arrested in G0 & can AP Biology never divide  Activation of cell division  How do cells know when to divide?  cell communication signals  chemical signals in cytoplasm give cue  signals usually mean proteins  activators  inhibitors AP Biology “Go-ahead” signals  Protein signals that promote cell growth & division  internal signals  “promoting factors”  external signals  “growth factors”  Primary mechanism of control  phosphorylation  kinase enzymes  either activates or inactivates cell signals AP Biology  inactivated Cdk Cell cycle signals  Cell cycle controls  cyclins  regulatory proteins  levels cycle in the cell  Cdk’s activated Cdk  cyclin-dependent kinases  phosphorylates cellular proteins  activates or inactivates proteins  Cdk-cyclin complex  triggers passage through different stages of cell cycle AP Biology Cyclins & Cdks  Interaction of Cdk’s & different cyclins triggers the stages of the cell cycle AP Biology  Spindle checkpoint G2 / M checkpoint Chromosomes attached Replication completed at metaphase plate DNA integrity Inactive Active Active Inactive Cdk / G2 M APC cytokinesis cyclin (MPF) C G2 mitosis G1 S Cdk / G1 cyclin Inactive MPF = Mitosis Active Promoting Factor G1 / S checkpoint Growth factors APC = Anaphase Nutritional state of cell AP BiologyComplex Promoting Size of cell Cyclin & Cyclin-dependent kinases  CDKs & cyclin drive cell from one phase to next in cell cycle  proper regulation of cell cycle is so key to life that the genes for these regulatory proteins have been highly conserved through evolution  the genes are basically the same in yeast, insects, plants & animals (including humans) AP Biology  External signals  Growth factors  coordination between cells  protein signals released by body cells that stimulate other cells to divide  density-dependent inhibition  crowded cells stop dividing  each cell binds a bit of growth factor not enough activator left to trigger division in any one cell  anchorage dependence  to divide cells must be attached to a substrate AP Biology “touch sensor” receptors Growth factor signals growth factor nuclear pore nuclear membrane P P cell division cell surface Cdk receptor protein kinase P E2F cascade chromosome P P APcytoplasm Biology nucleus  Example of a Growth Factor  Platelet Derived Growth Factor (PDGF)  made by platelets in blood clots  binding of PDGF to cell receptors stimulates cell division in fibroblast (connective tissue)  heal wounds AP Biology Growth Factors and Cancer  Growth factors can create cancers  proto-oncogenes  normal growth factor genes that become oncogenes (cancer-causing) when mutated  stimulates cell growth  if switched “ON” can cause cancer  example: RAS (activates cyclins)  tumor-suppressor genes  inhibits cell division  if switched “OFF” can cause cancer  example: p53 AP Biology  Cancer & Cell Growth  Cancer is essentially a failure of cell division control  unrestrained, uncontrolled cell growth  What control is lost?  lose checkpoint stops  gene p53 plays a key role in G1/S restriction point  p53 protein halts cell division if it detects damaged DNA p53 is the  options: Cell Cycle stimulates repair enzymes to fix DNA Enforcer forces cell into G0 resting stage keeps cell in G1 arrest causes apoptosis of damaged cell  ALL cancers have to shut down p53 activity AP Biology p53 — master regulator gene NORMAL p53 p53 allows cells with repaired DNA to divide. p53 protein DNA repair enzyme p53 protein Step 1 Step 2 Step 3 DNA damage is caused Cell division stops, and p53 triggers the destruction by heat, radiation, or p53 triggers enzymes to of cells damaged beyond repair. chemicals. repair damaged region. ABNORMAL p53 abnormal p53 protein cancer Step 1 Step 2 cell DNA damage is The p53 protein fails to stop Step 3 caused by heat, cell division and repair DNA. Damaged cells continue to divide. radiation, or Cell divides without repair to If other damage accumulates, the damaged DNA. AP chemicals. Biology cell can turn cancerous.  Development of Cancer  Cancer develops only after a cell experiences ~6 key mutations (“hits”)  unlimited growth  turn on growth promoter genes  ignore checkpoints  turn off tumor suppressor genes (p53)  escape apoptosis  turn off suicide genes It’s like an  immortality = unlimited divisions out of control  turn on chromosome maintenance genes car!  promotes blood vessel growth  turn on blood vessel growth genes  overcome anchor & density dependence  turn off touch-sensor gene AP Biology What causes these “hits”?  Mutations in cells can be triggered by  UV radiation  cigarette smoke  chemical exposure  pollution  radiation exposure  age  heat  genetics AP Biology  Tumors  Mass of abnormal cells  Benign tumor  abnormal cells remain at original site as a lump  p53 has halted cell divisions  most do not cause serious problems & can be removed by surgery  Malignant tumors  cells leave original site  lose attachment to nearby cells  carried by blood & lymph system to other tissues  start more tumors = metastasis  impair functions of organs throughout body AP Biology Traditional treatments for cancers  Treatments target rapidly dividing cells  high-energy radiation  kills rapidly dividing cells  chemotherapy  stop DNA replication  stop mitosis & cytokinesis  stop blood vessel growth AP Biology