Unit 7 The Cell Cycle Cell Growth Cell

Unit 7 -The Cell Cycle: Cell Growth, Cell Division AP Biology 2007 -2008

Why do cells divide? § For reproduction u asexual reproduction § one-celled organisms § For growth u from fertilized egg to multi-celled organism § For repair & renewal u AP Biology replace cells that die from normal wear & tear or from injury amoeba

Making new cells § Nucleus chromosomes u DNA u § Cytoskeleton u centrioles § in animals u AP Biology microtubule spindle fibers

Centrioles § Cell division u in animal cells, pair of centrioles organize microtubules § spindle fibers u AP Biology guide chromosomes in mitosis

Getting the right stuff § What is passed on to daughter cells? u exact copy of genetic material = DNA § mitosis u organelles, cytoplasm, cell membrane, enzymes § cytokinesis chromosomes (stained orange) in kangaroo rat epithelial cell AP Biology notice cytoskeleton fibers

Overview of mitosis interphase prophase I. P. M. A. T. (pro-metaphase) cytokinesis AP Biology metaphase anaphase telophase

Interphase § 90% of cell life cycle u cell doing its “everyday job” § produce RNA, synthesize proteins/enzymes u prepares for duplication if triggered I’m working here! Time to divide & multiply! AP Biology

Cell cycle § Cell has a “life cycle” cell is formed from a mitotic division cell grows & matures to divide again G 1, S, G 2, M epithelial cells, blood cells, stem cells AP Biology cell grows & matures to never divide again liver cells G 1 G 0 brain / nerve cells muscle cells

Interphase § Divided into 3 phases: u l to a n sig ivide u d u G 1 = 1 st Gap (Growth) § cell doing its “everyday job” § cell grows S = DNA Synthesis § copies chromosomes G 2 = 2 nd Gap (Growth) § prepares for division § cell grows (more) § produces organelles, proteins, membranes AP Biology G 0

green = key features Interphase § Nucleus well-defined u DNA loosely packed in long chromatin fibers § Prepares for mitosis u replicates chromosome § DNA & proteins u AP Biology produces proteins & organelles

S phase: Copying / Replicating DNA § Synthesis phase of Interphase dividing cell replicates DNA u must separate DNA copies correctly to 2 daughter cells u § human cell duplicates ~3 meters DNA § each daughter cell gets complete identical copy § error rate = ~1 per 100 million bases w 3 billion base pairs in mammalian genome w ~30 errors per cell cycle n mutations (to somatic (body) cells) AP Biology

ACTGGTCAGGCAATGTC Organizing DNA § DNA is organized in chromosomes double helix DNA molecule u wrapped around histone proteins histones u § like thread on spools u DNA-protein complex = chromatin § organized into long thin fiber u condensed further during mitosis double stranded chromosome AP Biology duplicated mitotic chromosome

Copying DNA & packaging it… § After DNA duplication, chromatin condenses u coiling & folding to make a smaller package mitotic chromosome DNA chromatin AP Biology

double-stranded mitotic human chromosomes AP Biology

Mitotic Chromosome § Duplicated chromosome 2 sister chromatids u narrow at centromeres u contain identical copies of original DNA u homologous chromosomes single-stranded AP Biology sister chromatids double-stranded homologous = “same information”

Mitosis § Dividing cell’s DNA between 2 daughter nuclei u “dance of the chromosomes” § 4 phases prophase u metaphase u anaphase u telophase u AP Biology

green = key features Prophase § Chromatin condenses u visible chromosomes § chromatids § Centrioles move to opposite poles of cell u animal cell § Protein fibers cross cell to form mitotic spindle u microtubules § actin, myosin u coordinates movement of chromosomes § Nucleolus disappears § Nuclear membrane breaks down AP Biology

green = key features Transition to Metaphase § Prometaphase u spindle fibers attach to centromeres § creating kinetochores u microtubules attach at kinetochores § connect centromeres to centrioles u AP Biology chromosomes begin moving

green = key features Metaphase § Chromosomes align along middle of cell u metaphase plate § meta = middle spindle fibers coordinate movement u helps to ensure chromosomes separate properly u § so each new nucleus receives only 1 copy of each chromosome AP Biology

AP Biology

green = key features Anaphase § Sister chromatids separate at kinetochores move to opposite poles u pulled at centromeres u pulled by motor proteins “walking”along microtubules u § actin, myosin § increased production of ATP by mitochondria § Poles move farther apart u AP Biology polar microtubules lengthen

Separation of chromatids § In anaphase, proteins holding together sister chromatids are inactivated u separate to become individual chromosomes 1 chromosome 2 chromatids AP Biology double-stranded 2 chromosomes single-stranded

green = key features Telophase § Chromosomes arrive at opposite poles daughter nuclei form u nucleoli form u chromosomes disperse u § no longer visible under light microscope § Spindle fibers disperse § Cytokinesis begins u AP Biology cell division

Cytokinesis § Animals u constriction belt of actin microfilaments around equator of cell § cleavage furrow forms § splits cell in two § like tightening a draw string AP Biology

Cytokinesis in Animals AP Biology

Mitosis in whitefish blastula AP Biology

Mitosis in animal cells AP Biology

Cytokinesis in Plants § Plants u cell plate forms § vesicles line up at equator w derived from Golgi § vesicles fuse to form 2 cell membranes u AP Biology new cell wall laid down between membranes § new cell wall fuses with existing cell wall

Cytokinesis in plant cell AP Biology

onion root tip AP Biology

Evolution of mitosis § Mitosis in chromosome: double-stranded replication of DNA eukaryotes likely evolved from binary fission in bacteria single circular chromosome u no membranebound organelles u AP Biology Origin of replication elongation of cell ring of proteins cell pinches in two

Evolution of mitosis § A possible progression of mechanisms intermediate between binary fission & mitosis seen in modern organisms prokaryotes (bacteria) protists dinoflagellates protists diatoms eukaryotes yeast eukaryotes animals AP Biology

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

II. Meiosis § Definition: formation of § § a gamete with the haploid number of chromosomes also called reduction division Parent cell will divide twice to yield 4 daughter cells AP Biology

A. Stage I 1. Interphase I: the DNA replicates itself 2. Prophase I: a) fine threads of chromatin shorten and thicken b) chromosomes appear c) homologous chromosomes come together in pairs, a tetrad, each will contain 4 chromatids AP Biology

A. Stage I d) since the chromosomes are so close, they can exchange parts (crossing over) -this leads to variety in the offspring AP Biology

3. Metaphase I: a) tetrads line up down the middle of the cell AP Biology

A. Stage I 4. Anaphase I: a) 2 chromosomes from each tetrad move toward the opposite poles disjunction: separation of a tetrad AP Biology

A. Stage I 5. Telophase I: a) 2 daughter cells are produced with the haploid number of chromosomes AP Biology

B. stage II § No DNA replication, phases are exactly like mitosis § division of the cytoplasm and separation of chromatids § of each chromosome produces 4 daughter cells each with the haploid number of chromosomes (sex cells) AP Biology

More on Meiosis A. occurs in the production of sex cells (gametes) B. 2 cell divisions C. daughter cells contain one-half the number of the chromosomes the parent possesses AP Biology

A Comparison of Mitosis and Meiosis Point of Comparing # of Divisions Mitosis Meiosis One Two Recombination No Yes Number of Two daughter cells Genetic makeup Clones Four Function Sperm and egg for reproduction AP Biology Growth and repair Much different

There’s no turning back, now! Overview of Cell Cycle Control § Two irreversible points in cell cycle replication of genetic material u separation of sister chromatids u § Checkpoints u process is assessed & possibly halted centromere single-stranded AP Biology chromosomes sister chromatids double-stranded chromosomes

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/S § can DNA synthesis begin? u G 2/M § has DNA synthesis been completed correctly? § commitment to mitosis u spindle 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?

“Go-ahead” signals § Protein signals that promote cell growth & division u internal signals § “promoting factors” u external signals § “growth factors” § Primary mechanism of control u phosphorylation § kinase enzymes § either activates or inactivates cell signals AP Biology

inactivated Cdk Cell cycle signals § Cell cycle controls u cyclins § regulatory proteins § levels cycle in the cell u Cdks § cyclin-dependent kinases § phosphorylates cellular proteins w activates or inactivates proteins u activated Cdk-cyclin complex § triggers passage through different stages of cell cycle AP Biology

Cyclins & Cdks 1970 s-80 s | 2001 § Interaction of Cdk’s & different cyclins triggers the stages of the cell cycle AP Biology

Spindle checkpoint G 2 / M checkpoint Chromosomes attached at metaphase plate • Replication completed • DNA integrity Active Inactive Cdk / G 2 cyclin (MPF) M Active APC C cytokinesis mitosis G 2 G 1 S MPF = Mitosis Promoting Factor APC = Anaphase AP Biology. Complex Promoting Cdk / G 1 cyclin Active G 1 / S checkpoint Inactive • Growth factors • Nutritional state of cell • 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 u the genes are basically the same in yeast, insects, plants & animals (including humans) u AP Biology

External signals § Growth factors u u coordination between cells protein signals released by body cells that stimulate other cells to divide § density-dependent inhibition w crowded cells stop dividing w each cell binds a bit of growth factor n not enough activator left to trigger division in any one cell § anchorage dependence w to divide cells must be attached to a substrate n “touch sensor” receptors AP Biology

Growth factor signals growth factor nuclear pore nuclear membrane P P cell division cell surface receptor protein kinase cascade Cdk E 2 F P P Rb 2 F E APcytoplasm Biology chromosome P Rb nucleus

Example of a Growth Factor § Platelet Derived Growth Factor (PDGF) u u made by platelets in blood clots binding of PDGF to cell receptors stimulates cell division in connective tissue § heal wounds Don’t forget to mention erythropoietin! (EPO) AP Biology

Growth Factors and Cancer § Growth factors can create cancers u proto-oncogenes § 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 tumor-suppressor genes § 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 — 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 changes (“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