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  1. The Cell Cycle

  2. Outline • The Cell Cycle • Interphase • Mitotic Stage • Cell Cycle Control • Apoptosis • Mitosis & Cytokinesis • Mitosis in Animal Cells • The Cell Cycle & Cancer • Prokaryotic Cell Division

  3. The Cell Cycle • An orderly set of stages and substages between one division and the next • Just prior to next division: • The cell grows larger • The number of organelles doubles • The DNA is replicated • Major stages of the cell cycle: • G1 – S – G2 (comprise Interphase ) • Mitosis (redistribution of DNA as chromosomes and division of the cytoplasm) Cells have a massive job to do before they can divide!

  4. The Cell Cycle Cells spend most of their time in Interphase, preparing for division.

  5. Interphase (3 distinct phases) • (Most of the cell cycle is spent in interphase) • G1 Phase: 1st Growth phase • Recovery from previous division • Cell doubles its organelles • Accumulates raw materials for DNA synthesis • S Phase: Synthesis phase • DNA replication (synthesis) • Chromosomes enter with 1 chromatid each • Chromosomes leave with 2 identical chromatids each G2 Phase: 2nd Growth phase • Between DNA replication and onset of mitosis • Cell synthesizes proteins necessary for division If a cell is fully differentiated and does not need to replicate (i.e. nerve cells) then it pauses or stays in G1/G0. Cells need a growth signal to enter synthesis phase. Once this phase is entered a cell is generally committed to division: many growth signals are “oncogenes” …..see diagram. Cells pause in G2 to check DNA for errors and repair them.

  6. Mitotic (M) phase. • Characterized by to stages: • Mitosis – replication and division of DNA - characterized by several phases: prophase-metaphase – anaphase - telophase • At completion, daughter nuclei contain equal numbers of replicated chromosomes • Cytokinesis (division of the cell) • Division furrow divides the cytoplasm • Results in two genetically identical daughter cells PMAT

  7. Cell Cycle Control • Cell cycle controlled by internal and external signals • External signals • Growth factors (ex: Somatomedins, hGF, NGF..) • Received at the plasma membrane • Initiate a transition from G1 to S. Once in S a cell is committed to the rest of the cycle. • Internal signals • Cyclins: a family of proteins that regulate cell cycle progression. • Increase and decrease as cell cycle continues • When cyclins are low, cell cycle stops at G1. Oocytes (eggs) naturally stop at M or G2 • Cyclins are part of DNA damage monitoring.

  8. Regulation of the cell cycle SUMMARY: Cells leave interphase when MPF (= maturation promoting factor = mitosis promoting factor = cdc2 kinase) activity is activated by a high level of cyclins.

  9. Cell cycle regulation (cont’d) Checkpoint controls p21 wee1 wee2 Cdk 25 Rb = Retinoblastoma gene P53 tumor suppressor gene Oncogenes

  10. Mitosis:Preparation (DNA must be packaged) • DNA is in very long threads • Chromosomes • Stretched out and intertangled between divisions • DNA is organized and packaged with histone proteins • Collectively called chromatin • Before mitosis begins: • Chromatin condenses (coils) into distinctly visible chromosomes • Each species has a characteristic chromosome number • Humans 46 • Corn 20 • Goldfish 94 In Prophase: DNA is condensed and tightly packaged by being wrapped around proteins called histones.

  11. Chromatin – “beads on a string” Loosely packaged DNA is called chromatin.

  12. Condensation and packing of DNA Question: How is about 1 meter of DNA organized and packed into the nucleus which is about 5um in diameter? NB. This would be like trying to pack 570 miles of garden hose (x2) into the front seat of your car.

  13. Terminology:Chromosome Number • Most familiar organisms are diploid, having received one paternal copy and one maternal copy of each chromosome (plus an X and a Y) • Human somatic cells have 22 pairs of autosomes, plus two sex chromosome ( X, Y) for a total of 46. • Only gametes (sperm and eggs) have one set of autosomes (haploid)

  14. n – number: • The number of unique chromosome is designated as the ‘n’ number: Example, the human n number is 23. • Examples: • Gametes are 1n (i.e. Haploid, 23 chromosomes per nucleus) • Somatic cells are 2n: 2 x 23 = 46 chromosomes per nucleus. • One set of 23 from individual’s father (paternal) • Other set of 23 from individual’s mother (maternal)

  15. Chromosome Numbersof Some Eukaryotes

  16. Chromosome duplication and separation. • At end of S phase: • chromosomes have been duplicated. • Each duplicated chromosome is termed a Sister chromatid • Sister chromatids are attached together at a single point (centromere) • During mitosis: • Centromeres holding sister chromatids together simultaneously break • Sister chromatids separate and are then termed daughter chromosomes. • Daughter chromosomes of each type are distributed to opposite daughter nuclei.

  17. Duplicated Chromosome

  18. Mitosis in Animal Cells • Just outside nucleus is the centrosome: • This is the microtubule organizing center (MTOC) • Organizes the mitotic spindle which is a bundle of microtubules responsible for separating daughter chromosomes. • MTOC in animals, contains two barrel-shaped centrioles. • Oriented at right angles to each other within centrosome • Each with 9 triplets of microtubules arranged in a cylinder • Centrosome is also replicated in S-phase, so there are two centrosomes at the beginning of M-phase.

  19. Prophase • Prophase • Chromatin condenses • Chromosomes distinguishable with microscope • Visible double (two sister chromatids attached at centromere) • Nuclear envelope disintegrates (NEB = nuclear envelope breakdown) • Spindle begins to take shape • Two centrosomes move away from each other • Form microtubules in star-like arrays – asters

  20. Mitosis in Animals

  21. Prometaphase • Prometaphase • Centromere of each set of sister-chromatids develops two kinetochores. • Specialized protein complex over each sister chromatid that physically hook sister chromatids up with specialized microtubules of the mitotic spindle. • These connect daughter chromosomes to opposite poles of mother cell

  22. Metaphase & Anaphase • Metaphase • Chromosomes are pulled around by kinetochore fibers • Forced to align across equatorial plane of cell • Appear to be spread out on a piece of glass • Metaphase plate • Represents plane through which mother cell will be divided • Anaphase • Centromere dissolves, releasing sister chromatids • Sister chromatids separate • Now called daughter chromosomes • Pulled to opposite poles along kinetochore fibers

  23. Telophase • Telophase • Spindle disappears • Now two clusters of daughter chromosomes • Still two of each type with all types represented • Clusters are incipient daughter nuclei • Nuclear envelopes form around the two incipient daughter nuclei • Chromosomes uncoil and become diffuse chromatin again • Nucleolus reappears in each daughter nucleus

  24. Cytokinesis:Animal Cells • Division of cytoplasm • Allocates mother cell’s cytoplasm equally to daughter nucleus • Encloses each in it’s own plasma membrane • Often begins in anaphase • Animal cytokinesis: • A cleavage furrow appears between daughter nuclei • Formed by a contractile ring of actin filaments • Like pulling on a draw string • Eventually pinches mother cell in two

  25. Cytokinesis in Animal Cells

  26. Cytokinesis:Plant Cells • Rigid cell walls outside plasma membrane do not permit furrowing • Begins with formation of a cell plate • Many small membrane-bounded vesicles • Eventually fuse into one thin vesicle extending across the mother cell • The membranes of the cell plate become the plasma membrane between the daughter cells • Contents of vesicles become the middle lamella between the two daughter cells • Daughter cells later secrete primary cell walls on opposite sides of middle lamella

  27. Cytokinesis in Plant Cells

  28. Contrast Meiosis / Mitosis Meiosis = Reductive division. Cells go from 1N to 2N

  29. Meiosis and gametes: In most animals, meiosis only occurs in germ cells that Give rise to gametes. 1N 1N 2N

  30. Apoptosis: Programmed cell death • Mitosis and apoptosis are opposing forces • Mitosis increases cell number • Apoptosis decreases cell number • Cells harbor apoptosis enzymes (caspases) • Ordinarily held in check by inhibitors • Can be unleashed by internal or external signals • Signal protein P53 • Stops cycle at G2 when DNA damaged • Initiates DNA attempt at repair • If successful, cycle continues to mitosis • If not, apoptosis is initiated

  31. Apoptosis

  32. The Cell Cycle and Cancer • Abnormal growth of cells is called a neoplasm • Benign neoplasms are not cancerous • Encapsulated • Do not invade neighboring tissue or spread • Malignant neoplasms are cancerous • Not encapsulated • Readily invade neighboring tissues • May also detach and lodge in distant places = metastasis • Results from mutation of genes regulating the cell cycle • Carcinogenesis – development of cancer • Tends to be gradual • May be years before cell is obviously cancerous

  33. Characteristics of Cancer Cells • Lack differentiation • Have abnormal nuclei • Form tumors • Mitosis controlled by contact with neighboring cells – contact inhibition • Cancer cells have lost contact inhibition • Undergo metastasis • Original tumor easily fragments • New tumors appear in other organs • Undergo angiogenesis • Formation of new blood vessels

  34. Cancer Cells Versus Normal Cells

  35. Cancer Cells

  36. Origins of Cancer:Oncogenes • Mutations in DNA repair mechanisms • Oncogenes • Proto-oncogenes promote the cell cycle in various ways • Tumor suppressor genes inhibit the cell cycle in various ways • Both normally regulated in coordination with organism’s growth plan • If either mutates, may lose control and become oncogene

  37. Origins of Cancer:Telomerase • Chromosomes normally have special material at each end called telomeres (end parts) • These get shorter each cell division • When they get very short • The cell will no longer divide • Almost like running out of division tickets • Telomerase is an enzyme that adds telomeres • Mutations in telomerase gene: • Keeps adding new telomeres • Allow cancer cells to continually divide • Like counterfeit tickets

  38. Causes of Cancer

  39. Prokaryotic Cell Division • Prokaryotic chromosome a ring of DNA • Folded up in an area called the nucleoid • 1,000 X length of cell • Replicated into two rings prior to division • Replicate rings attach to plasma membrane • Binary fission • Splitting in two between the two replicate chromosomes • Produces two daughter cells identical to original cell – Asexual Reproduction

  40. Binary Fission of Prokaryotes

  41. Review • The Cell Cycle • Interphase • Mitotic Stage • Cell Cycle Control • Apoptosis • Mitosis & Cytokinesis • Mitosis in Animal Cells • The Cell Cycle & Cancer • Prokaryotic Cell Division

  42. The Cell Cycle

  43. The Cell Cycle

  44. Reduction in Chromosome Number Terminology Meiosis Overview Genetic Variation Crossing-Over Independent Assortment Fertilization Phases of Meiosis Meiosis I Meiosis II Meiosis Compared to Mitosis Human Life Cycle Outline Alleles, homologues, heterozygous, homozygous The importance of meiosis and what it accomplishes The three major contributors to genetic variation

  45. Homologous Chromosomes Homologues refer to the “identical” pairs of chromosomes we inherit, one from our mothers and one from our fathers.

  46. Homologous copies of a gene may encode identicalordiffering genetic information The variants that exist for a gene are called alleles Alleles may be: a). Homozygous Identical alleles for a specific gene on both homologs. b) Heterozygous maternal allele and paternal alleles are different (i.e. 1of 25 people are heterozygous for cystic fibrosis) Homologous Pairs ofChromosomes

  47. Germline cells undergo a specialized form of cell division called meiosis. Meiosis is important because: It reduces the cells genetic content from 2nto n It increases genetic variation by employing two strategies: SYANAPSIS: “shuffling” genes between maternal and paternal alleles INDEPENDANT ASSORTMENT: maternal and paternal homologues line-up (metaphase) and separate (anaphase) in a random fashion Meiosis (overview)

  48. Overview of Meiosis

  49. Meiosis I (reductional division): (PMAT) Prophase 1 Metaphase 1  Anaphase 1 Teloph. Phases of Meiosis I:Prophase I & Metaphase I Centromeres remain intact Sister chromosomes Do Not separate Synapsis and Independent Assortment of homologues

  50. Cytokinesis I Homologues have separated, therefore daughter cells are now HAPLOID! Interkinesis Similar to mitotic interphase, shorter duration NO DNA REPLICATION. Phases of Meiosis I:Cytokinesis I & Interkinesis