Chapter 9 The Cell Cycle & Mitosis

Limits to Size• Why can’t organisms just be one giant cell?

– Diffusion cannot occur quickly and efficiently if the distances involved become too large.• wastes would collect inside the cell and poison it• nutrients could not reach organelles in time, so

cells would die– Information flow would not would occur

efficiently.• DNA does not make copies as a cell grows – what it

starts with is all that it has• Must be enough DNA blueprint to allow for

protein production

Ratio of Surface Area to Volume in Cells

Volume is a three-dimensional unit – length X width X height

Surface Area is a two-dimensional unit – length X width

SO VOLUME INCREASES AT A FASTER RATE THAN DOES SURFACE AREA…Thus, SURFACE AREA IS THE LIMITING FACTOR IN THE SIZE OF A CELL

Functions of Cell Division1. Reproduction of cells

– all cells come from pre-existing cells– results in two identical cells except for size

2. Growth and Development of Organisms– tadpoles become frogs, ivy vines get longer

3. Tissue renewal– skin cells are being replaced, cuts and bruises heal

Cell Division: Distributing Identical Sets of Chromosomes to Daughter Cells

• Key to cell division is the copying and equal separation of chromosomes:– Chromosomes are carriers of the

genetic material that is copied and passed from generation to generation:

• made up of DNA and protein• cells of every organism have

a specific number of chromosomes

• not visible in cells except during cell division

Cell Division• Before it becomes too large, a growing somatic cell

divides forming 2 “daughter” cells by a process known as cell division– Each daughter cell gets 1 complete set of genetic

information during cell division and therefore will be IDENTICAL TO THE MOTHER CELL!

A somatic cell is a non sex cell!

Time Span of Mitotic Cell Division

• varies from one organism type to another– humans - interphase - 16-20 hours– mitosis - 1 hour

• occurs more rapidly in unspecialized cells (early embryos).

• specialized cells (nerve cells) seldom or never divide.

Chromosomes

• Spend most of their time as Chromatin – long strands of DNA that are wrapped around proteins and appear hazy and unorganized through the microscope – this loose arrangement is necessary for copying to occur. – When a cell gets ready to divide, the chromatin coils

and condenses into what we call Chromosomes.• When visible, chromosomes consist of two

identical Sister Chromatids that are joined in the center at the Centromere

Chromosomes• In eukaryotic cells, the genetic

information that is passed on from one generation of cells to the next is carried by chromosomes– Chromosomes are made of DNA– The cells of every organism have a

specific number of chromosomes (human cells have 46 chromosomes)

• Before cell division, each chromosome is replicated and consists of 2 identical “sister” chromatids– Each pair of chromatids is attached at

an area called the centromeres

centromeres

sister chromatids

Chromosome Number is Species Specific

• Humans- 46• Fruit flies- 8• Crayfish- 20• Potato- 48• Orangutans- 48

Each duplicated chromosome has two sister chromatids, which separate during cell division

0.5 µm

Chromosomeduplication(including DNA synthesis)

Centromere

Separation of sister

chromatids

Sisterchromatids

Centromeres Sister chromatids

A eukaryotic cell has multiplechromosomes, one of which is

represented here. Before duplication, each chromosome

has a single DNA molecule.

Once duplicated, a chromosomeconsists of two sister chromatids

connected at the centromere. Eachchromatid contains a copy of the

DNA molecule.

Mechanical processes separate the sister chromatids into two chromosomes and distribute

them to two daughter cells.

Figure 12.4

A duplicating chromosome consists of 2 sister chromatids, which narrow at their centromeres. The DNA molecules of sister chromatids are identical.

Chromosomes normally exist in the highly condensed state shown here only during the process of mitosis.

The Cell Cycle- IPMAT

• During the cell cycle, a cell grows, prepares for division, and divides to form 2 daughter cells, where each one of which begins a new cycle.

• The 5 phases of the cell cycle are:1. Interphase – period of rest between cell division

2. Prophase3. Metaphase4. Anaphase5. Telophase

Cytokinesis (division of the cytoplasm) begins in anaphase and is completed at the end of telophase.

phases of nuclear division (MITOSIS)

Events of the Cell Cycle

nuclear division

M Phase

cell divides

Events of the Cell Cycle

Interphase is divided into 3 phases:1. G1 – cell growth (protein synthesis, organelle production)2. S – DNA replication- 2 identical chromatids are produced3. G2 – preparation for Mitosis

• During Interphase, chromosomes are in their “uncondensed” form and are called chromatin

Mitosis (nuclear division) is the division of the nucleus and it occurs in 4 phases:

4. P = prophase – chromatin condenses into chromosomes, the centrioles separate & nuclear membrane breaks down

5. M = metaphase – chromosomes line up across center of cell and each chromosome is connected to a spindle fiber at its centromere

6. A = anaphase – sister chromatids separate into individual chromosomes and are pulled apart

7. T = telophase – chromosomes gather at opposite ends of the cell and 2 new nuclear membranes form around them

Cytokinesis – division of cytoplasm

includes

is divided into is divided into

Concept Map of all events of Cell Cycle

Cell Cycle

M phase (Mitosis)

Interphase

G1 phase S phase ProphaseG2 phase Metaphase TelophaseAnaphase

Go to Section:

Interphase: G1, S, and G2

• Interphase is very long (cells spend most of time here)…

– G1 phase – cell growth; cells increase in size and synthesize new proteins and organelles

– S phase – chromosomes are replicated and the synthesis of DNA molecules takes place; key proteins associated with the chromosomes are synthesized during this time

– G2 phase – shortest of 3 phases; many of the organelles and molecules required for cell division are produced

INTERPHASE- G2

Nucleus well defined bounded by nuclear envelope.

Easily identifiable nucleolus.

Genetic material in uncondensed form of chromatin. – chromosomes cannot be seen.

2 centrosomes adjacent to nucleus, formed earlier by replication of a single centrosome

In animals, a pair of centrioles in each centrosome

In animals, a radial microtubular array called an aster forms around each pair of centrioles

Centrosomes are microtubule organizing centers!

M phase: Mitosis - PMAT

• Prophase• Metaphase• Anaphase• Telophase

• http://www.sumanasinc.com/webcontent/animations/content/mitosis.html

Prophase: 1st and Longest Phase

• In Nucleus-• Chromatin coils and condenses – becomes visible as

chromosomes composed of 2 identical chromatids joined at the centromere;

• nucleolus disappears, nuclear membrane breaks down• In cytoplasm-

• Mitotic spindle forms. It is composed of microtubules between 2 centrosomes or microtubule organizing centers.

• Centrosomes( with centriole)s separate, apparently propelled along the nuclear surface by lengthening of the microtubule bundles between them, and take up positions on opposite sides of the nucleus ;

• chromosomes become attached to spindle fibers;

PROPHASE

Prometaphase• Nuclear envelope fragments, which

allows microtubules to interact with the highly condensed chromosomes.

• Spindle fibers (bundles of microtubules) extend from each pole toward the cell’s equator.

• Each chromatid now has a specialized structure, the kinetochore, located in the centromere region.

• Kinetochore microtubules become attached to kinetochores and put the chromosomes into agitated motion

• Nonkinetochore microtubules radiate from each centrosome toward the metaphase plate without attaching to chromosomes. Nonkinetochore microtubules radiating from one pole ovrerlap with those from the opposite pole.

“Middle” Metaphase: Shortest Phase

• Centrosomes are positioned at opposite poles• Chromosomes line up in center of cell along

metaphase plate, or equator.• For each chromosome, the kinetochores on

centromeres of the sister chromatids are attached to microtubles coming from opposite poles of the cell

• Entire structure formed by nonkinetochore microtubules plus kinetochore microtubules is called the spindle.

Figure 12.6 The mitotic spindle at metaphase

Anaphase “Apart”• Anaphase begins suddenly when the paired

centromeres that join the sister chromatids separate from each other.

• NOW EACH CHROMATID IS A SEPARATE CHROMOSOME….they begin moving toward opposite poles of the cell.

• Kinetochore microtubules shorten at the kinetochore end as chromosomes approach the poles.

• Simultaneously, the poles of the cell move farther apart, elongating the cell.

• Chromosomes continue to move until they have separated into two groups near the poles of the spindle.

• Anaphase is over when the chromosomes stop moving!

Figure 9.9

Kinetochore

Experiment

Spindlepole

Results

Kinetochore

Conclusion

Mark

Tubulinsubunits

Chromosome

Motorprotein

Chromosomemovement

Microtubule

The microtubules shorten by depolymerizing at their kinetochore endsChromosomes are also “reeled in” by motor proteins at spindle poles, and microtubules depolymerize after they pass by the motor proteins

At which end do kinetochore microtubules shorten during anaphase?

Telophase: Final Phase of Mitosis

• Nonkinetochore microtubules further elongate the cell.

• Two daughter nuclei form at the two poles of the cell.• Chromosomes begin to relax back down into

chromatin.• Nuclear envelope re-forms around each cluster of

chromatin.• Spindle begins to break apart and nucleolus reappears

in each daughter cell• MITOSIS IS NOW COMPLETE, BUT NOT CELL DIVISION!

Figure 12.5x Mitosis

Cytokinesis

• Division of the cytoplasm itself.• Begins in late anaphase and is completed in

telophase.– Can take place in a number of ways:

• in animal cells – “draw-string” effect by microfilaments forms cleavage furrow (which pinches the cell into two parts)

• in plant cells – cell plate forms from inside out, and cell wall begins to appear

CYTOKINESIS

Figure 12.8 Cytokinesis in animal and plant cells

Figure 12.5 The stages of mitotic cell division in an animal cell: G2 phase; Prophase; Prometaphase

Figure 12.5 The stages of mitotic cell division in an animal cell: Metaphase; Anaphase; Telophase and Cytokinesis.

Plant Cell VS Animal Cell Mitosis

• Mitosis is almost the same with two differences-– Plants do have centrosomes but lack centrioles.– Plant cell do not form asters

• Mitosis in a plant cell

1 Prophase. The chromatinis condensing. The nucleolus is beginning to disappear.Although not yet visible in the micrograph, the mitotic spindle is staring to from.

Prometaphase.We now see discretechromosomes; each consists of two identical sister chromatids. Laterin prometaphase, the nuclear envelop will fragment.

Metaphase. The spindle is complete,and the chromosomes,attached to microtubulesat their kinetochores, are all at the metaphase plate.

Anaphase. Thechromatids of each chromosome have separated, and the daughter chromosomesare moving to the ends of cell as their kinetochoremicrotubles shorten.

Telophase. Daughternuclei are forming. Meanwhile, cytokinesishas started: The cellplate, which will divided the cytoplasm in two, is growing toward the perimeter of the parent cell.

2 3 4 5

NucleusNucleolus

ChromosomeChromatinecondensing

Figure 12.10

Binary Fission• Prokaryotes (bacteria)

– Reproduce by a type of cell division called binary fission

– In binary fission- The bacterial chromosome replicates

– The two daughter chromosomes actively move apart

Figure 9.12-4

1

Origin ofreplication

Two copiesof origin

Bacterialchromosome

Plasmamembrane

Cell wall

E. coli cell

Origin Origin

Chromosomereplicationbegins.

2

3

4

One copy of theorigin is now ateach end of thecell.

Replicationfinishes.

Two daughtercells result.

The Evolution of Mitosis

• Since prokaryotes preceded eukaryotes by billions of years– It is likely that mitosis evolved from bacterial cell

division• Certain protists

– Exhibit types of cell division that seem intermediate between binary fission and mitosis carried out by most eukaryotic cells

• A hypothetical sequence for the evolution of mitosis

Most eukaryotes. In most other eukaryotes, including plants and animals, the spindle forms outside the nucleus, and the nuclear envelope breaks down during mitosis. Microtubules separate the chromosomes, and the nuclear envelope then re-forms.

Dinoflagellates. In unicellular protists called dinoflagellates, the nuclear envelope remains intact during cell division, and the chromosomes attach to the nuclear envelope. Microtubules pass through the nucleus inside cytoplasmic tunnels, reinforcing the spatial orientation of the nucleus, which then divides in a fission process reminiscent of bacterial division.

Diatoms. In another group of unicellular protists, the diatoms, the nuclear envelope also remains intact during cell division. But in these organisms, the microtubules form a spindle within the nucleus. Microtubules separate the chromosomes, and the nucleus splits into two daughter nuclei.

Prokaryotes. During binary fission, the origins of the daughter chromosomes move to opposite ends of the cell. The mechanism is not fully understood, but proteins may anchor the daughter chromosomes to specific sites on the plasma membrane.

(a)

(b)

(c)

(d)

Bacterialchromosome

Microtubules

Intact nuclear envelope

Chromosomes

Kinetochore microtubules

Intact nuclearenvelope

Kinetochore microtubules

Fragments ofnuclear envelope

Centrosome

Figure 12.12 A-D

How do cells know when to divide?• Cells stop dividing when there is a shortage of

nutrients.• When the cell comes in contact with a solid surface• Feedback mechanism - when # of cells is normal,

concentration of control substance that they secrete prevents cell division, when # of cells decreases the control sub. also decreases, thus permitting cell division to occur until cell # is normal.

• Growth factors also control cell growth• Presence of proteins called CYCLINS:

– 2 types: • internal regulators• external regulators

Close Contact Between Cells

WHEN CELLS COME INTO CONTACT WITH OTHER CELLS, THEY STOP GROWING!

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

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Cyclins• Regulate the timing of the cell cycle in

eukaryotic cells– TYPES:

• Internal regulators: respond to events inside the cell;

– Ex. Don’t begin mitosis until all chromosomes are copied

• External regulators: respond to events outside the cell; direct cells to speed up or slow down the cell cycle.

– Ex. Growth factors that stimulate the growth and division of cells are external regulators

Figure 9.14

G1 nucleusimmediately enteredS phase and DNAwas synthesized.

Experiment

Experiment 1 Experiment 2

Results

S

SS

MG1

MM

G1

G1 nucleus beganmitosis withoutchromosomeduplication.

Conclusion Molecules present in the cytoplasmcontrol the progression to S and M phases.

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 washing machine

– The washing machine has specific checkpoints- Where the cell cycle stops until a go-ahead signal is received

Figure 12.14

Control system

G2 checkpoint

M checkpoint

G1 checkpoint

G1

S

G2M

In Super Mario, you must pass checkpoints for your game to save

Figure 9.16

M checkpoint

G1

G1 checkpoint

M

G1

G2

Without go-ahead signal,cell enters G0.

G0

With go-ahead signal,cell continues cell cycle.

(a) G1 checkpoint

Prometaphase

G1

M G2

Without full chromosomeattachment, stop signal isreceived.

(b) M checkpoint

S

G1

M

G1

G2

G2

checkpoint

Metaphase

Anaphase

With full chromosomeattachment, go-ahead signalis received.

The Cell Cycle Clock: Cyclins and Cyclin-Dependent Kinases

• Two types of regulatory proteins are involved in cell cycle control

• Cyclins and cyclin-dependent kinases (Cdks)

• The activity of cyclins and Cdks– Fluctuates during the cell cycle

During G1, conditions in the cell favor degradation of cyclin, and the Cdk component of MPF is recycled.

5

During anaphase, the cyclin component of MPF is degraded, terminating the M phase. The cell enters the G1 phase.

4

Accumulated cyclin moleculescombine with recycled Cdk mol-ecules, producing enough molecules of MPF to pass the G2 checkpoint and initiate the events of mitosis.

2

Synthesis of cyclin begins in late S phase and continues through G2. Because cyclin is protected from degradation during this stage, it accumulates.

1

Cdk

CdkG2

checkpoint

CyclinMPF

Cyclin is degraded

DegradedCyclin

G 1

G 2

S

M

G1G1 S G2 G2SM MMPF activity

Cyclin

Time

(a) Fluctuation of MPF activity and cyclin concentration during the cell cycle

(b) Molecular mechanisms that help regulate the cell cycle

MPF promotes mitosis by phosphorylating various proteins. MPF‘s activity peaks during metaphase.

3

Figure 12.16 A, B

M

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

• 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

Figure 9.17-4

1 A sample ofhuman connectivetissue is cutup into smallpieces.

2

3

4

Enzymes digestthe extracellularmatrix, resultingin a suspension offree fibroblasts.

Cells are transferredto culture vessels. PDGF is added to

half the vessels.

Without PDGF With PDGF Cultured fibroblasts(SEM) 10 m

Petridish

Scalpels

The effect of platelet-derived growth factor (PDGF) on cell division (step 4)

• Another example of external signals is density-dependent 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

Figure 9.18

Anchorage dependence: cellsrequire a surface for division

20 m

Density-dependent inhibition:cells divide to fill a gap andthen stop

Density-dependent inhibition:cells form a single layer

20 m

(a) Normal mammalian cells (b) Cancer cells

Loss of Cell Cycle Controls in Cancer Cells

• Cancer cells do not respond to signals that normally regulate the cell cycle

• Cancer cells may 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

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• 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 can metastasize, exporting cancer cells to other parts of the body, where they may form additional tumors

• Malignant tumors invade surrounding tissues and can metastasize– Exporting cancer cells to other parts of the body

where they may form secondary tumors

Cancer cells invade neighboring tissue.

2 A small percentage of cancer cells may survive and establish a new tumor in another part of the body.

4Cancer cells spread through lymph and blood vessels to other parts of the body.

3A tumor grows from a single cancer cell.

1

Tumor

Glandulartissue

Cancer cell

Bloodvessel

Lymphvessel

MetastaticTumor

Figure 12.19

Figure 12-17x1 Breast cancer cell

Figure 12-17x2 Mammogram: normal (left) and cancerous (right)

Treatments for Cancer:

• surgery• radiation therapy – expose to radiation

– releases free ions/free radicals, these attach to DNA, prevents cell division

• chemotherapy – causes nausea, lowering of immune system due to healthy cells that are affected– venchristine – attaches to mitotic spindle– methotrexate – anti-metabolite attaches to DNA, prevents DNA

from replicating• used to treat leukemia, brain tumors, testicular tumors