Chapter 19
The Cell Cycle, DNA
Replication, and Mitosis
• Cells must be able to grow and divide.
– Cell growth: the synthesis of
• Protein, nucleic acids, carbohydrates
and lipids
– Cell division
• Increases the cell number
The Cell Cycle: DNA Replication,
Mitosis, and Cancer
 • An Overview of the Cell Cycle
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DNA Replication
DNA Damage and Repair
Nuclear and Cell Division
Regulation of the Cell Cycle
Growth Control and Cancer
An Overview of the Cell Cycle
• Cell growth – accompanied by cell division
• Single-called organisms- increase cell mass
• Multicellular organisms- increase cell mass,
growth of the organism, replace the cell
• Mitotic (M) phase- the division process
– Mitosis- nuclear division
– Cytokinesis- the division of the cytoplasm to
produce two daughter cells
An Overview of the Cell Cycle
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Sister chromatids(姊妹染色分體)
Centromere﹙中節﹚
Mitotic spindle﹙紡垂體﹚
Interphase﹙間期﹚: most cell contents are
synthesized continuously and cell mass is also increase
• Cell cycle- G1 phase, S phase, G2 phase, M phase
• Generation time: S phase = 6 – 8 hr; M phase = 30 – 45
min; G2 phase = 4 - 6 hr; G1 = 8 – 10 phase (typical) but
varies in different species; G0 phase
Doubling Time (DT)
( t - t0 ) x Log 2
DT =
Log N - Log N0
t0 =起始時間；t = 結束時間
N0 = 起始細胞數
The Cell Cycle: DNA Replication,
Mitosis, and Cancer
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An Overview of the Cell Cycle
DNA Replication
DNA Damage and Repair
Nuclear and Cell Division
Regulation of the Cell Cycle
Growth Control and Cancer
The Key Roles of Cell Division
• Cell division functions in reproduction,
growth, and repair
• Cell division distributes identical sets of
chromosomes to daughter cells
Cell Division Functions in Reproduction,
Growth, and Repair
• Cell division requires the distribution of identical
genetic material - DNA - to two daughter cells.
– What is remarkable is the fidelity with which DNA is
passed along, without dilution, from one generation to
the next.
• A dividing cell duplicates its DNA, allocates the
two copies to opposite ends of the cell, and then
splits into two daughter cells.
Cell Division Distributes Identical Sets
of Chromosomes to Daughter Cells
• A cell’s genetic information, packaged as DNA,
is called its genome.
– In prokaryotes, the genome is often a single long
DNA molecule.
– In eukaryotes, the genome consists of several DNA
molecules.
• A human cell must duplicate DNA and separate
the two copies such that each daughter cell ends
up with a complete genome.
• Each eukaryotic chromosome consists of a long,
linear DNA molecule.
• Each chromosome has hundreds or thousands of
genes, the units that specify an organism’s
inherited traits.
• Associated with DNA are proteins that maintain
its structure and help control gene activity.
• This DNA-protein complex, chromatin, is
organized into a long thin fiber.
• After the DNA duplication, chromatin condenses,
coiling and folding to make a smaller package.
Equilibrium Density Centrifugation Shows
That DNA Replication is Semi-Conservative
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Equilibrium density centrifugation:
Density gradient centrifugation:
Equilibrium density centrifugation in
DNA analysis:
Semiconservation replication of densitylabeled DNA
The Cell Cycle: DNA Replication,
Mitosis, and Cancer
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•
•
 •
•
•
An Overview of the Cell Cycle
DNA Replication
DNA Damage and Repair
Nuclear and Cell Division
Regulation of the Cell Cycle
Growth Control and Cancer
Nuclear and cell division
• Mitotic phase (M phase)
– Mitosis (有絲分裂) : nuclear division
– Cytokinesis (細胞質分裂): cytoplasmic
division
• During interphase the cell grows by producing
proteins and cytoplasmic organelles, copies its
chromosomes, and prepares for cell division.
• Interphase has three subphases:
– the G1 phase (“first gap”) centered on growth,
– the S phase (“synthesis”) when the chromosomes
are copied,
– the G2 phase (“second gap”) where the cell
completes preparations for cell division,
– and M phase ： cell divides into two daughter cells.
• The daughter cells may then repeat the cycle.
• Cytokinesis in plants, which have cell walls,
involves a completely different mechanism.
• During telophase, vesicles
from the Golgi coalesce at
the metaphase plate,
forming a cell plate
(細胞板).
- The plate enlarges until its
membranes fuse with the
plasma membrane at the
perimeter, with the contents
of the vesicles forming new
wall material in between.
The mitotic spindle distributes
chromosomes to daughter cells
• The mitotic spindle, fibers composed of
microtubules and associated proteins, is a major
driving force in mitosis.
• As the spindle assembles during prophase, the
elements come from partial disassembly of the
cytoskeleton.
• The spindle fibers elongate by incorporating more
subunits of the protein tubulin.
The Cell Cycle: DNA Replication,
Mitosis, and Cancer
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•
•
•
 •
•
An Overview of the Cell Cycle
DNA Replication
DNA Damage and Repair
Nuclear and Cell Division
Regulation of the Cell Cycle
Growth Control and Cancer
• The timing and rates of cell division in different
parts of an animal or plant are crucial for normal
growth, development, and maintenance.
• The frequency of cell division varies with cell
type.
– Some human cells divide frequently throughout life
(skin cells), others have the ability to divide, but keep
it in reserve (liver cells), and mature nerve and
muscle cells do not appear to divide at all after
maturity.
• Investigation of the molecular mechanisms
regulating these differences provide important
insights into how normal cells operate, but also
how cancer cells escape controls.
• Not run out of nutrients or space
• Regulated to meet the needs of a particular
cell types or species
• Regulation mechanism- controlling
mechanism: molecular mechanisms (cancer
cell escape from normal control system)
The length of the cell cycle varies
among different cell types
• Generation times are different among different cell
types
• Variation based on differences in G1: some very
long (G0), some very short (no G1)
– Long G1: nerve or muscle cell
– Very short G1 or no G1: embryonic cells of
insect, amphibians: very short S phase, also
very short in G2
– Cell growth need not to be part of the cell
cycle
• A checkpoint in the cell cycle is a critical
control point where stop and go signals regulate
the cycle.
– Many signals registered at checkpoints come from
cellular surveillance mechanisms .
– These indicate whether key cellular processes have
been completed correctly.
– Checkpoint also register signals from outside the
cell.
• Three major checkpoints are found in the G1,
G2, and M phases.
• For many cells, the G1 checkpoint, the
restriction point in mammalian cells, is the most
important.
– If the cells receives a go-ahead signal, it
usually completes the cell cycle and divides.
– If it does not receive a go-ahead signal, the
cell exits the cycle and switches to a
nondividing state, the G0 phase.
• Most human cells are in this phase.
• Highly specialized nerve and muscle cells
never divide.
The cell cycle is controlled by cyclindependent kinase (cdk) molecules
• Rhythmic fluctuations in the abundance and
activity of control molecules pace the cell cycle.
– Some molecules are protein kinases that activate or
deactivate other proteins by phosphorylating them.
• The levels of these kinases are present in
constant amounts, but these kinases require a
second protein, a cyclin (細胞週期素), to
become activated.
– Level of cyclin proteins fluctuate cyclically.
– The complex of kinases and cyclin forms cyclindependent kinases (Cdks).
The Regulation of Cdk-cyclin Complexes
• Different kinds of cyclins are sythesized
and degraded during different phases of the
cell cycle.
• The activity of Cdk-cyclin complexes is
controlled by phosphorylation and
dephosphorylation reactions catalyzed by
protein kinases and phosphatases.
The Cell Cycle: DNA Replication,
Mitosis, and Cancer
•
•
•
•
•
 •
An Overview of the Cell Cycle
DNA Replication
DNA Damage and Repair
Nuclear and Cell Division
Regulation of the Cell Cycle
Growth Control and Cancer
Growth Control and Cancer
• Cells usually live in nutrient-rich
environment
• How to control cell division that would be a
big and serious problem: Growth factors
• Most of growth factors are mitogens
Cancer involves defective cell cycle
control mechanisms
• Tumor
• Benign tumor (良性)
• Malignant tumor- Cancer
– Spontaneous DNA mutations and replication errors
– Mutant genes that contribute to the development of
cancer can also be inherited
• Cancer-inducing mutations involve three main classes of
genes
– Oncogenes: a gene can trigger the development of
cancer- mutation from normal cellular gene
– Tumor suppressor genes
– DNA repair genes
Oncogenes arise from proto-oncogenes
• Proto-oncogenes: normal cellular genes
• Most oncogenes are mutant forms of normal cellular
genes (proto-oncogenes)
• The mechanisms of mutation
– Point Mutation
– DNA rearrangement: Local DNA rearrangement cause either
deletions or base-sequence exchanges between protooncogenes and surrounding genes
– Gene amplification: Increasing the number of copies of a
particular proto-oncogene- over-produce the normal protein
– Chromosmal translocation: A portion of one chromosome is
physically removed and joined to another chromosome
Cancer can arise from the loss of tumor suppressor
genes that normally restrain cell regulation
• The Rb gene: The Rb gene codes for the Rb
protein, whose role in controlling the transition
from G1 to S phase
• The p53 gene and apoptosis
– The most frequently mutated gene in human cancer
– The accumulation of p53 concentration can activate
two kinds of events:
• Arrest in G1: gives cells time to repair DNA damage- p53
stimulate the production of enzymes for DNA repair
• Apoptosis: If DNA can not be repaired then apoptosis
Genetic instability leads to the
accumulation of multiple mutation in
cancer cells
Aneuploid:因為細胞內基因不穩定，在細胞分裂時造
非整倍體 成染色體不正常的分離，而致使染色體數
不正常，這種現象稱之。
Can Cancer Growth be Stopped?
• Angiogenesis
• Invasion
• Metastasis
Growth Factors and Cell Proliferation
• Stimulatory Growth Factors Activate the
Ras Pathway
• Stimulatory Growth Factors Can Also
Activate the PI3k-Akt Pathway
• Inhibitory Growth Factors Act Through cdk
inhibitors
Inhibitory Growth Factors Act
Through cdk Inhibitors
• Transforming growth factor- (TGF-): can
be growth-stimulating or growth-inhibiting
properties, depending on the cell type
• TGF- (as growth-inhibitor) binds to
receptor and triggers a series of events that
increases a inhibiting protein, called p15 or
p21: Cdk inhibitor