The Cell Cycle CAMPBELL BIOLOGY IN FOCUS SECOND EDITION URRY CAIN WASSERMAN MINORSKY REECE

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1 CAMPBELL BIOLOGY IN FOCUS URRY CAIN WASSERMAN MINORSKY REECE 9 The Cell Cycle Lecture Presentations by Kathleen Fitzpatrick and Nicole Tunbridge, Simon Fraser University SECOND EDITION

2 Overview: The Key Roles of Cell Division The ability of organisms to produce more of their own kind best distinguishes living things from nonliving matter The continuity of life is based on the reproduction of cells, or cell division

3 Figure 9.1

4 In unicellular organisms, division of one cell reproduces the entire organism Cell division enables multicellular eukaryotes to develop from a single cell and, once fully grown, to renew, repair, or replace cells as needed Cell division is an integral part of the cell cycle, the life of a cell from its formation to its own division

5 Figure m (a) Reproduction 50 m (b) Growth and development 20 m (c) Tissue renewal

6 Figure m (a) Reproduction

7 Figure (b) Growth and development 50 m

8 Figure m (c) Tissue renewal

9 Concept 9.1: Most cell division results in genetically identical daughter cells Most cell division results in the distribution of identical genetic material DNA to two daughter cells DNA is passed from one generation of cells to the next with remarkable fidelity

10 Cellular Organization of the Genetic Material All the DNA in a cell constitutes the cell s genome A genome can consist of a single DNA molecule (common in prokaryotic cells) or a number of DNA molecules (common in eukaryotic cells) DNA molecules in a cell are packaged into chromosomes

11 Figure m

12 Eukaryotic chromosomes consist of chromatin, a complex of DNA and protein Every eukaryotic species has a characteristic number of chromosomes in each cell nucleus Somatic cells (nonreproductive cells) have two sets of chromosomes Gametes (reproductive cells: sperm and eggs) have one set of chromosomes

13 Distribution of Chromosomes During Eukaryotic Cell Division In preparation for cell division, DNA is replicated and the chromosomes condense Each duplicated chromosome has two sister chromatids, joined identical copies of the original chromosome The centromere is where the two chromatids are most closely attached

14 Figure 9.4 Sister chromatids Centromere 0.5 m

15 During cell division, the two sister chromatids of each duplicated chromosome separate and move into two nuclei Once separate, the chromatids are called chromosomes

16 Figure 9.5-s1 Chromosomes Chromosomal DNA molecules Centromere Chromosome arm

17 Figure 9.5-s2 Chromosomes Chromosomal DNA molecules Centromere Chromosome arm Chromosome duplication Sister chromatids

18 Figure 9.5-s3 Chromosomes Chromosomal DNA molecules Centromere Chromosome arm Chromosome duplication Sister chromatids Separation of sister chromatids

19 Eukaryotic cell division consists of Mitosis, the division of the genetic material in the nucleus Cytokinesis, the division of the cytoplasm Gametes are produced by a variation of cell division called meiosis Meiosis yields nonidentical daughter cells that have only one set of chromosomes, half as many as the parent cell

20 Concept 9.2: The mitotic phase alternates with interphase in the cell cycle In 1882, the German anatomist Walther Flemming developed dyes to observe chromosomes during mitosis and cytokinesis

21 Phases of the Cell Cycle The cell cycle consists of Mitotic (M) phase, including mitosis and cytokinesis Interphase, including cell growth and copying of chromosomes in preparation for cell division

22 Interphase (about 90% of the cell cycle) can be divided into subphases G 1 phase ( first gap ) S phase ( synthesis ) G 2 phase ( second gap ) The cell grows during all three phases, but chromosomes are duplicated only during the S phase

23 Figure 9.6 ER G 1 S (DNA synthesis) G 2

24 Mitosis is conventionally divided into five phases Prophase Prometaphase Metaphase Anaphase Telophase Cytokinesis overlaps the latter stages of mitosis

25 Figure m G 2 of Interphase Centrosomes (with centriole pairs) Chromosomes (duplicated, uncondensed) Prophase Early mitotic Centromere spindle Aster Fragments of nuclear envelope Prometaphase Nonkinetochore microtubules Nucleolus Nuclear envelope Plasma membrane Two sister chromatids of one chromosome Kinetochore Kinetochore microtubules

26 Figure m Metaphase Anaphase Telophase and Cytokinesis Metaphase plate Cleavage furrow Nucleolus forming Spindle Centrosome at one spindle pole Daughter chromosomes Nuclear envelope forming

27 Figure G 2 of Interphase Centrosomes (with centriole pairs) Chromosomes (duplicated, uncondensed) Prophase Early mitotic Centromere spindle Aster Nucleolus Nuclear envelope Plasma membrane Two sister chromatids of one chromosome

28 Figure Fragments of nuclear envelope Prometaphase Nonkinetochore microtubules Metaphase Metaphase plate Kinetochore Kinetochore microtubules Spindle Centrosome at one spindle pole

29 Figure Anaphase Telophase and Cytokinesis Cleavage furrow Nucleolus forming Daughter chromosomes Nuclear envelope forming

30 Figure m G 2 of Interphase

31 Figure m Prophase

32 Figure m Prometaphase

33 Figure m Metaphase

34 Figure m Anaphase

35 Figure m Telophase and Cytokinesis

36 The Mitotic Spindle: A Closer Look The mitotic spindle is a structure made of microtubules and associated proteins It controls chromosome movement during mitosis In animal cells, assembly of spindle microtubules begins in the centrosome, a type of microtubule organizing center

37 The centrosome replicates during interphase, forming two centrosomes that migrate to opposite ends of the cell during prophase and prometaphase An aster (radial array of short microtubules) extends from each centrosome The spindle includes the centrosomes, the spindle microtubules, and the asters

38 During prometaphase, some spindle microtubules attach to the kinetochores of chromosomes and begin to move the chromosomes Kinetochores are protein complexes that assemble on sections of DNA at centromeres At metaphase, the centromeres of all the chromosomes are at the metaphase plate, an imaginary structure at the midway point between the spindle s two poles

39 Figure 9.8 Sister chromatids Aster Centrosome Metaphase plate (imaginary) Kinetochores Microtubules Chromosomes Overlapping nonkinetochore microtubules Kinetochore microtubules 1 m 0.5 m Centrosome

40 Figure Microtubules Chromosomes 1 m Centrosome

41 Figure Kinetochores Kinetochore microtubules 0.5 m

42 In anaphase, sister chromatids separate and move along the kinetochore microtubules toward opposite ends of the cell The microtubules shorten by depolymerizing at their kinetochore ends Chromosomes are also reeled in by motor proteins at spindle poles, and microtubules depolymerize after they pass by the motor proteins

43 Figure 9.9 Experiment Kinetochore Results Spindle pole Mark Conclusion Microtubule Chromosome movement Motor protein Chromosome Kinetochore Tubulin subunits

44 Figure Experiment Kinetochore Spindle pole Mark

45 Figure Results Conclusion Microtubule Chromosome movement Motor protein Chromosome Kinetochore Tubulin subunits

46 Nonkinetochore microtubules from opposite poles overlap and push against each other, elongating the cell At the end of anaphase, duplicate groups of chromosomes have arrived at opposite ends of the elongated parent cell Cytokinesis begins during anaphase or telophase, and the spindle eventually disassembles

47 Cytokinesis: A Closer Look In animal cells, cytokinesis occurs by a process known as cleavage, forming a cleavage furrow In plant cells, a cell plate forms during cytokinesis

48 Animation: Cytokinesis

49 Figure 9.10 (a) Cleavage of an animal cell (SEM) (b) Cell plate formation in a plant cell (TEM) Cleavage furrow 100 m Vesicles forming cell plate Wall of parent cell Cell plate 1 m New cell wall Contractile ring of microfilaments Daughter cells Daughter cells

50 Figure Cleavage furrow 100 m

51 Figure Vesicles forming cell plate Wall of parent cell 1 m

52 Figure 9.11 Nucleus Nucleolus Chromosomes condensing Chromosomes 10 m Prophase Prometaphase Cell plate Metaphase Anaphase Telophase

53 Figure Nucleus Nucleolus Chromosomes condensing 10 m Prophase

54 Figure Chromosomes 10 m Prometaphase

55 Figure m Metaphase

56 Figure m Anaphase

57 Figure Cell plate Telophase 10 m

58 Binary Fission in Bacteria Prokaryotes (bacteria and archaea) reproduce by a type of cell division called binary fission In E. coli, the single chromosome replicates, beginning at the origin of replication The two daughter chromosomes actively move apart while the cell elongates The plasma membrane pinches inward, dividing the cell into two

59 Figure 9.12-s1 Chromosome replication begins. Origin of replication E. coli cell Two copies of origin Cell wall Plasma membrane Bacterial chromosome

60 Figure 9.12-s2 Chromosome replication begins. Origin of replication E. coli cell Two copies of origin Cell wall Plasma membrane Bacterial chromosome One copy of the origin is now at each end of the cell. Origin Origin

61 Figure 9.12-s3 Chromosome replication begins. Origin of replication E. coli cell Two copies of origin Cell wall Plasma membrane Bacterial chromosome One copy of the origin is now at each end of the cell. Origin Origin Replication finishes.

62 Figure 9.12-s4 Chromosome replication begins. Origin of replication E. coli cell Two copies of origin Cell wall Plasma membrane Bacterial chromosome One copy of the origin is now at each end of the cell. Origin Origin Replication finishes. Two daughter cells result.

63 The Evolution of Mitosis Since prokaryotes evolved before eukaryotes, mitosis probably evolved from binary fission Certain protists (dinoflagellates, diatoms, and some yeasts) exhibit types of cell division that seem intermediate between binary fission and mitosis

64 Figure 9.13 Chromosomes Microtubules (a) Dinoflagellates Intact nuclear envelope Kinetochore microtubule Intact nuclear envelope (b) Diatoms and some yeasts

65 Concept 9.3: The eukaryotic cell cycle is regulated by a molecular control system The frequency of cell division varies with the type of cell These differences result from regulation at the molecular level Cancer cells manage to escape the usual controls on the cell cycle

66 Evidence for Cytoplasmic Signals The cell cycle is driven by specific signaling molecules present in the cytoplasm Some evidence for this hypothesis comes from experiments with cultured mammalian cells Cells at different phases of the cell cycle were fused to form a single cell with two nuclei at different stages Cytoplasmic signals from one of the cells could cause the nucleus from the second cell to enter the wrong stage of the cell cycle

67 Figure 9.14 Experiment Experiment 1 Experiment 2 S G 1 M G 1 Results S S M M G 1 nucleus immediately entered S phase and DNA was synthesized. G 1 nucleus began mitosis without chromosome duplication. Conclusion Molecules present in the cytoplasm control the progression to S and M phases.

68 Checkpoints of the Cell Cycle Control System The sequential events of the cell cycle are directed by a distinct cell cycle control system, which is similar to a timing device of a washing machine The cell cycle control system is regulated by both internal and external controls The clock has specific checkpoints where the cell cycle stops until a go-ahead signal is received

69 Figure 9.15 G 1 checkpoint G 1 Control system S M G 2 M checkpoint G 2 checkpoint

70 For many cells, the G 1 checkpoint seems to be the most important If a cell receives a go-ahead signal at the G 1 checkpoint, it will usually complete the S, G 2, and M phases and divide If the cell does not receive the go-ahead signal, it will exit the cycle, switching into a nondividing state called the G 0 phase

71 Figure 9.16 G 1 checkpoint G 0 G 1 G 1 G 1 S Without go-ahead signal, cell enters G 0. (a) G 1 checkpoint With go-ahead signal, cell continues cell cycle. M G 2 G 1 G 1 M G 2 M G 2 M checkpoint Anaphase G 2 checkpoint Prometaphase Without full chromosome attachment, stop signal is received. (b) M checkpoint Metaphase With full chromosome attachment, go-ahead signal is received.

72 Figure G 1 checkpoint G 0 G 1 Without go-ahead signal, cell enters G 0. (a) G 1 checkpoint G 1 With go-ahead signal, cell continues cell cycle.

73 Figure G 1 G 1 M G 2 M G2 M checkpoint Anaphase G 2 checkpoint Prometaphase Without full chromosome attachment, stop signal is received. (b) M checkpoint Metaphase With full chromosome attachment, go-ahead signal is received.

74 The cell cycle is regulated by a set of regulatory proteins and protein complexes including kinases and proteins called cyclins

75 An example of an internal signal occurs at the M phase checkpoint In this case, anaphase does not begin if any kinetochores remain unattached to spindle microtubules Attachment of all of the kinetochores activates a regulatory complex, which then activates the enzyme separase Separase allows sister chromatids to separate, triggering the onset of anaphase

76 Some external signals are growth factors, proteins released by certain cells that stimulate other cells to divide For example, platelet-derived growth factor (PDGF) stimulates the division of human fibroblast cells in culture

77 Figure 9.17-s1 A sample of human connective tissue is cut up into small pieces. Petri dish Scalpels

78 Figure 9.17-s2 A sample of human connective tissue is cut up into small pieces. Petri dish Scalpels Enzymes digest the extracellular matrix, resulting in a suspension of free fibroblasts.

79 Figure 9.17-s3 A sample of human connective tissue is cut up into small pieces. Petri dish Scalpels Enzymes digest the extracellular matrix, resulting in a suspension of free fibroblasts. Cells are transferred to culture vessels. Without PDGF

80 Figure 9.17-s4 A sample of human connective tissue is cut up into small pieces. Petri dish Scalpels Enzymes digest the extracellular matrix, resulting in a suspension of free fibroblasts. Cells are transferred to culture vessels. PDGF is added to half the vessels. Without PDGF With PDGF Cultured fibroblasts (SEM) 10 m

81 Figure Cultured fibroblasts (SEM) 10 m

82 Another example of external signals is densitydependent inhibition, in which crowded cells stop dividing Most animal cells also exhibit anchorage dependence, in which they must be attached to a substratum in order to divide Cancer cells exhibit neither density-dependent inhibition nor anchorage dependence

83 Figure 9.18 Anchorage dependence: cells require a surface for division Density-dependent inhibition: cells form a single layer Density-dependent inhibition: cells divide to fill a gap and then stop 20 m (a) Normal mammalian cells 20 m (b) Cancer cells

84 Figure m (a) Normal mammalian cells

85 Figure m (b) Cancer cells

86 Loss of Cell Cycle Controls in Cancer Cells Cancer cells do not respond to signals that normally regulate the cell cycle Cancer cells do not need growth factors to grow and divide They may make their own growth factor They may convey a growth factor s signal without the presence of the growth factor They may have an abnormal cell cycle control system

87 A normal cell is converted to a cancerous cell by a process called transformation Cancer cells that are not eliminated by the immune system form tumors, masses of abnormal cells within otherwise normal tissue If abnormal cells remain only at the original site, the lump is called a benign tumor Malignant tumors invade surrounding tissues and undergo metastasis, exporting cancer cells to other parts of the body, where they may form additional tumors

88 Figure m Breast cancer cell (colorized SEM) Tumor Lymph vessel Blood vessel Metastatic tumor Glandular tissue Cancer cell A tumor grows from a single cancer cell. Cancer cells invade neighboring tissue. Cancer cells spread through lymph and blood vessels to other parts of the body. A small percentage of cancer cells may metastasize to another part of the body.

89 Figure Tumor Lymph vessel Blood vessel A tumor grows from a single cancer cell. Glandular tissue Cancer cells invade neighboring tissue. Cancer cell Cancer cells spread through lymph and blood vessels to other parts of the body.

90 Figure Lymph vessel Blood vessel Metastatic tumor Cancer cell Cancer cells spread through lymph and blood vessels to other parts of the body. A small percentage of cancer cells may metastasize to another part of the body.

91 Figure m Breast cancer cell (colorized SEM)

92 Recent advances in understanding the cell cycle and cell cycle signaling have led to advances in cancer treatment Medical treatments for cancer are becoming more personalized to an individual patient s tumor

93 Figure 9.UN01-1 Number of cells A Control Treated B C A B C Amount of fluorescence per cell (fluorescence units) Data from K. K. Velpula et al., Regulation of glioblastoma progression by cord blood stem cells is mediated by downregulation of cyclin D1, PLoS ONE 6(3): e18017 (2011). doi: /journal.pone

94 Figure 9.UN01-2 Human glioblastoma cell

95 Figure 9.UN02 P Cytokinesis Mitosis G 1 G 2 S MITOTIC (M) PHASE Telophase and Cytokinesis Anaphase Metaphase Prometaphase Prophase

96 Figure 9.UN03

97 Figure 9.UN04