Cell Division and Mitosis
Quote
 “Although
memorizing of the phases of
mitosis has tortured students for decades,
understanding how these events actually
occur continue to occupy cell biologists, as
a complete molecular model has yet to be
obtained”


S. Gadde and R. Heald
Current Biology 14:R797-R805 (2004)
The Cycle of Cell Growth and
Division:
An Overview
 The
products of mitosis are genetic
duplicates of the dividing cell
 Chromosomes
are the genetic units
divided by mitosis
Mitotic Cell Division
 DNA
replication
 Equal
separation (segregation) of
replicated DNA molecules
 Delivery

to daughter cells
Two new cells, same information as parent
cell
Mitosis
 Mitosis


is the basis for
Growth and maintenance of body mass in
multicelled eukaryotes
Reproduction of many single-celled
eukaryotes
Chromosomes
 DNA
of eukaryotic cells is divided among
individual, linear chromosomes

Located in cell nucleus
 Ploidy


of a cell or species
Diploid (2n)
Haploid (n)
Eukaryotic Chromosomes
 Eukaryotic
cells contain 2 sets of
chromosomes = homologous pairs
 Diploid – 2 sets of chromosomes

Autosomal cells
 Haploid

– 1 set of chromosomes
Reproductive cells (egg, sperm)
Eukaryotic Chromosomes
Fig. 10-2, p. 203
Sister Chromatids
 DNA
replication and duplication of
chromosomal proteins produces two exact
copies (sister chromatids)
 Chromosome
cell division
segregation occurs during
The Mitotic Cell Cycle
 Interphase
extends from the end of one
mitosis to the beginning of the next mitosis
 After
interphase, mitosis proceeds in five
stages
 Cytokinesis
completes cell division by
dividing the cytoplasm between daughter
cells
 The
mitotic cell cycle is significant for both
development and reproduction
 Mitosis
varies in detail, but always
produces duplicate nuclei
Mitotic Cell Cycle
 Includes
 Mitosis





mitosis and interphase
occurs in five stages
Prophase
Prometaphase
Metaphase
Anaphase
Telophase
The Cell Cycle
Fig. 10-3, p. 203
Checkpoints
**
Interphase
Fig. 10-4a (1), p. 204
Fig. 10-4b, p. 205
Stage 1: Prophase
 Chromosomes
 Spindle
condense into short rods
forms in the cytoplasm
Prophase
Fig. 10-4a (2), p. 204
Stage 2: Prometaphase
 Nuclear


envelope breaks down
Spindle enters former nuclear area
Sister chromatids of each chromosome
connect to opposite spindle poles
 Kinetochore
of each chromatid attaches to
the spindle microtubules
Prometaphase
Fig. 10-4a, p. 204
Spindle Connections at
Prometaphase
Fig. 10-6, p. 206
Prometaphase chromosome
Sister
chromatid I
Sister
chromatid II
Kinetochore I
Spindle pole
Kinetochore II
Spindle
microtubules
Spindle pole
Fig. 10-6, p. 206
Stage 3: Metaphase
 Spindle
is fully formed
 Chromosomes

align at metaphase plate
Moved by spindle microtubules
Metaphase
Fig. 10-4b, p. 204
Stage 4: Anaphase
 Spindle
separates sister chromatids and
moves them to opposite spindle poles
 Chromosome
segregation is complete
Anaphase
Fig. 10-4b, p. 204
Stage 5: Telophase
 Chromosomes

decondense
Return to extended state typical of interphase
 New
nuclear envelope forms around
chromosomes
Telophase
Fig. 10-4b, p. 204
Mitosis
Fig. 10-5, p. 206
Cytokinesis
 Division
of cytoplasm completes cell
division
 Produces

two daughter cells
Each daughter nucleus produced by mitosis
Cytokinesis in Animal Cells
 Proceeds


by furrowing
Band of microfilaments just under the plasma
membrane contracts
Gradually separates cytoplasm into two parts
Cytokinesis by Furrowing
Fig. 10-8, p. 208
Plant Cytokinesis
 Cell
wall material is deposited along the
plane of the former spindle midpoint
 Deposition
continues until a continuous
new wall (cell plate) separates daughter
cells
Cytokinesis by Cell Plate
Formation
Fig. 10-9, p. 208
Chromosomes in
the Cell Cycle
At what part of the
cell cycle would you
see a chromosome
that looks like this?
Give your reasons.
Rate of Mitosis
If you were to examine a sample of
connective tissue cells from a small but adult
mammal and a second sample from a fetus
of the same species, in which would you
expect to find more cells undergoing
mitosis?
Why?
Formation and Action of
the Mitotic Spindle
 Animals
and plants form spindles in
different ways
 Mitotic
spindles move chromosomes by a
combination of two mechanisms
Spindle Formation
 In


 In

animal cells
Centrosome divides, the two parts move apart
Microtubules of the spindle form between them
plant cells with no centrosome
Spindle microtubules assemble around the
nucleus
Centrosome and Spindle
Formation
Fig. 10-10, p. 210
In the Spindle
 Kinetochore

microtubules
Run from poles to kinetochores of
chromosomes
 Nonkinetochore

microtubules
Run from poles to a zone of overlap at the
spindle midpoint without connecting to
chromosomes
A Fully Developed Spindle
Fig. 10-11, p. 210
During Anaphase
 Kinetochores
move along kinetochore
microtubules

Pulling chromosomes to the poles
 Nonkinetochore
microtubules slide over each
other

Pushing the poles farther apart
Anaphase Spindle Movements
Fig. 10-12, p. 211
Kinetochore Movement
Fig. 10-13, p. 211

Current Biology
14:R797-R805
(2004)
Latest research
 Science
311:388-391 (2006)
 Kapoor Lab
Cell Cycle Regulation
 Cyclins

Internal controls that directly regulate cell
division
 Internal

and cyclin-dependent kinases
checkpoints
Stop cell cycle if stages are incomplete
 External

controls
Coordinate mitotic cell cycle of individual cells
within overall activities of the organism
Control of the cell cycle
is based on
cyclically activated
protein kinases
Phosphorylation of key proteins that
regulate DNA replication
(S phase), Mitosis (M phase), and
Cytokinesis
CDK
Cyclin/CDK
Phosphorylation
Cell Cycle Control
 Complexes
of cyclin and a cyclindependent protein kinase (CDK)

Directly control cell cycle
 CDK


Is activated when combined with a cyclin
Adds phosphate groups to target proteins,
activating them
Cell Cycle Control
 Activated
proteins trigger the cell to
progress to the next cell cycle stage
 Each


major stage of the cell cycle
Begins with activation of one or more
cyclin/CDK complexes
Ends with deactivation of complexes by
breakdown of cyclins
Cyclin/CDK Control
Fig. 10-15, p. 214
Cyclin B
Cyclin B
CDK1
G2-to-M
checkpoint
CDK1
Cyclin E
G2-to-S
checkpoint
Cyclin E
CDK2
CDK2
Stepped Art
Fig. 10-15, p. 214
Human cells CDK and cyclin
Internal Controls
 Important
internal controls create
checkpoints

Ensure that the reactions of one stage are
complete before cycle proceeds to next stage
External Controls
 Based
on surface receptors that recognize
and bind signals



Peptide hormones and growth factors
Surface groups on other cells
Molecules of the extracellular matrix
 Binding
triggers internal reactions that
speed, slow, or stop cell division
Cancer is a genetic
disease
Accumulation of mutations in key
regulatory genes resulting in
abnormal growth control
Metastatic lung tumors in a human liver
Genomic Instability
Loss of growth control results in
genomic instability
Genomic Instability
Science 297:544 (2002)
Cancer
 Control


of cell division is lost
Cells divide continuously and uncontrollably
Form rapidly growing mass of cells that
interferes with body functions
 Cancer
cells break loose from their original
tumor (metastasize)

Form additional tumors in other parts of the
body
Tumor Cells
Fig. 10-16, p. 215
Human cells CDK and cyclin
Targeted drugs:
Tyrosine kinase inhibitors
 Herceptin

for the treatment of metastatic breast cancer
 Gleevec

(imatinib mesylate)
for the treatment of chronic myelogenous
leukemia (CML)
 Avastin

(trastuzumab)
(bevacizumab)
for the treatment of metastatic colorectal
cancer
Targeted Therapies
Her-2/neu as breast cancer target
 HER2


(human EGFR-related gene)
Amplified up to 100X in tumor cells of about
30% of patients with invasive breast cancer
Significant clinical correlation between gene
amplification and reduced survival
Herceptin
 Therapeutic
monoclonal antibody (mAb)
Targeted drugs:
Tyrosine kinase inhibitors
 Herceptin

for the treatment of metastatic breast cancer
 Gleevec

(imatinib mesylate) Novartis
for the treatment of chronic myelogenous
leukemia (CML)
 Avastin

(trastuzumab) Genentech
(bevacizumab) Genentech
for the treatment of metastatic colorectal
cancer
Targeted Therapies
Gleevec
 Bcr-abl



kinase
Constitutively active cytoplasmic tyrosine
kinase
Present in virtually all patients with CML
activates signal transduction pathways
leading to uncontrolled cell growth
 Gleevec
blocks ATP binding to the kinase
Gleevec resistance
– 20% of patients who take Gleevec
become resistant to it within 3 years
 Bcr-abl mutations in the ATP binding
pocket of the kinase domain
 15
Targeted drugs:
Tyrosine kinase inhibitors
 Herceptin

for the treatment of metastatic breast cancer
 Gleevec

(imatinib mesylate) Novartis
for the treatment of chronic myelogenous
leukemia (CML)
 Avastin

(trastuzumab) Genentech
(bevacizumab) Genentech
for the treatment of metastatic colorectal
cancer
Targeted Therapies
Angiogenesis
New blood vessel formation
Dr. Judah Folkman
Avastin
 Binds
to VEGF (vascular endothelial
growth factor)
Future
 New

diagnostic tools
(cellular/gene based testing) -predictors of which treatment works best
on which person
Nature 415:532 (2002)
Future
 Combinatorial


therapies
Combine an anti-EGFR mAb and
tyrosine kinase inhibitor within the cell
Erbitux (ImClone) with Tarceva
(Genentech)
Future
 “Promiscuous”




drugs
SU11248 (Pfizer)
Interferes with several signaling
pathways
Anti-tumor and antiangiogenic
properties
Inhibits a variety of kinase receptors
Cell Division in Prokaryotes
 Replication
occupies most of the cell cycle
in rapidly dividing prokaryotic cells
 Replicated
chromosomes are distributed
actively to the halves of the prokaryotic
cell
 Mitosis
has evolved from binary fission
Replication in Prokaryotes
 Begins
at origin of replication of the
bacterial chromosome

Reactions catalyzed by enzymes in middle of
cell
 Once

the origin of replication is duplicated
Two origins migrate to two ends of the cells
Cytoplasmic Division
A
partition of cell wall material grows
inward until the cell is separated into two
parts
Bacterial Cell Division
Fig. 10-17, p. 216
Video: Mitosis overview