Mitosis and the Cell Cycle

Chapter 12 The Cell Cycle: Cell Growth & Cell Division

Where it all began…

• You started as a cell smaller than a period at the end of a

sentence…

Getting from there to here…

• Cell division

o Continuity of life = Reproduction of cells

� reproduction

• unicellular organisms

� growth

� repair & renew

• Cell cycle

o Life of a cell from origin to division into 2 new

daughter cells

Getting the right stuff

• What is passed to daughter cells?

o Exact copy of genetic material = DNA

� This division step = mitosis

o Assortment of organelles & cytoplasm

� This division step = cytokinesis

Copying DNA

• Dividing cell duplicates DNA

o Separates each copy to opposite ends of cell

o Splits into 2 daughter cells

� Human cell duplicates ~3 meters DNA

� Separates 2 copies so each daughter cell has complete

identical copy

� Error rate = ~1 per 100 million bases

• 3 billion base pairs in the mammalian genome

• ~30 errors per cell cycle called mutations

A bit about DNA

• DNA is organized in chromosomes

o Double helix DNA molecule

o Associated proteins = histone proteins

o DNA-protein complex = chromatin

� organized into long thin fiber

Copying DNA with care…

• After DNA duplication chromatin condenses

• Coiling & folding to make a smaller package

• From DNA to chromatin to highly condensed mitotic chromosome

Chromosome

• Duplicated chromosome consists of 2

sister chromatids

o Narrow at their centromeres

o Contain identical copies of the

chromosome’s DNA

Cell Division cycle

• Phases of a dividing cell’s life

o Interphase

• Cell grows

• Replicates chromosomes

• Produces new organelles &

biomolecules

o Mitotic phase

• Cell separates & divides

chromosomes

• Mitosis

• Cell divides cytoplasm &

organelles

• Cytokinesis

Interphase

• 90% of cell life cycle

o Cell doing its “everyday job”

� Produce RNA, synthesize

proteins

o Prepares for duplication if triggered

• Characteristics

o Nucleus well-defined

o DNA loosely packed in long chromatin

fibers

• Divided into 3 phases:

• G1 = 1st Gap

o cell doing its “everyday job”

o cell grows

• S = DNA Synthesis

o copies chromosomes

• G2 = 2nd Gap

o prepares for division

o cell grows

o produces organelles, proteins, membranes

Interphase G2

• Nucleus well-defined

o Chromosome duplication complete

o DNA loosely packed in long chromatin fibers

• Prepares for mitosis

o Produces proteins & organelles

Mitosis

• Copying cell’s DNA & dividing it between 2 daughter nuclei

• Mitosis is divided into 4 phases

o Prophase

o Metaphase

o Anaphase

o Telophase

Prophase

• Chromatin (DNA) condenses

o visible as chromosomes

� chromatids

o fibers extend from the centromeres

• Centrioles move to opposite poles of cell

• Fibers (microtubules) cross cell to form mitotic spindle

o actin, myosin

• Nucleolus disappears

• Nuclear membrane breaks down

Prometaphase

• Proteins attach to centromeres

o Creating kinetochores

• Microtubules attach at kinetochores

o Connect centromeres to centrioles

• Chromosomes begin moving

Kinetochore

• Each chromatid has own kinetochore proteins

o Microtubules attach to kinetochore proteins

Metaphase

• Spindle fibers align chromosomes along the middle of cell

o meta = middle

o metaphase plate

o helps to ensure chromosomes separate properly

o so each new nucleus receives only 1 copy of each

chromosome

Anaphase

• Sister chromatids separate at

kinetochores

o Separate to become

individual chromosomes

o Move to opposite poles

o Pulled at centromeres

o Pulled by motor proteins

“walking” along

microtubules

• Increased production of ATP by mitochondria

• Poles move farther apart

o Polar microtubules lengthen

Telophase

• Chromosomes arrive at opposite poles

o Daughter nuclei form

o Nucleoli from

o Chromosomes disperse

� No longer visible under light microscope

• Spindle fibers disperse

• Cytokinesis begins

o Cell division

Cytokinesis in Animals Cytokinesis in Plants

Cytokinesis in Plants

• Vesicles move to equator line up & fuse to form 2 membranes = cell plate

o Derived from Golgi

• New cell wall is laid down between membranes

o New cell wall fuses with existing cell wall

Evolution of Mitosis

• Mechanisms intermediate between binary fission & mitosis seen in modern organisms

o Protists

1

Regulation of Cell Division

Coordination of cell division

• Multicellular organism

o Need to coordinate across different parts of

organism

� Timing of cell division

� Rates of cell division

o Crucial for normal growth, development &

maintenance

� Do all cells have same cell cycle?

Frequency of cell division

• Frequency of cell division varies with cell type

o Skin cells

� divide frequently throughout life

o Liver cells

� retain ability to divide, but keep it in reserve

o Mature nerve cells & muscle cells

� do not divide at all after maturity

�

Cell Cycle Control

• Two irreversible points in cell cycle:

o Replication of genetic material.

o Separation of sister chromatids.

• Cell can be put on hold at specific checkpoints.

Checkpoint control system

• Checkpoints

o Cell cycle controlled by STOP & GO chemical

signals at critical points.

o Signals indicate if key cellular processes have been

completed correctly.

Checkpoint control system

• 3 major checkpoints:

o G1

• Can DNA synthesis begin?

o G2

• Has DNA synthesis been

completed correctly?

• Commitment to mitosis

o M phases

• Spindle checkpoint

• Can sister chromatids separate

correctly?

2

G1 checkpoint

• G1 checkpoint is most critical

o primary decision point

� “restriction point”

o If cell receives “go” signal, it divides

o If does not receive “go” signal, cell exits

cycle & switches to G0 phase

� non-dividing state

G0 phase

• Non-dividing, differentiated state

• Most human cells in G0 phase

o Liver cells

� In G0, but can be “called back” to cell cycle by external cues

o Nerve & muscle cells

o Highly specialized; arrested in G0 & can never

divide.

“Go-ahead” signals

• Signals that promote cell growth & division

o proteins

o internal signals

� “promoting factors”

o external signals

� “growth factors”

• Primary mechanism of control

o phosphorylation

� kinase enzymes

Protein signals

• Promoting factors

o Cyclins

� regulatory proteins

� levels cycle in the cell

o Cdks

� cyclin-dependent kinases

� enzyme activates cellular

proteins

o MPF

� maturation (mitosis)

promoting factor

o APC

� anaphase promoting complex

Cyclin & Cyclin dependent kinases

• CDKs & cyclin drive cell from one phase to next in cell cycle

o Proper regulation of cell cycle is so key to life that the genes for these regulatory proteins have

been highly conserved through evolution

� The genes are basically the same in yeast, insects, plants & animals (including humans)

3

External signals

• Growth factors: Protein signals released by

body cells that stimulate other cells to divide

Density-dependent inhibition

• Crowded cells stop

dividing

• Mass of cells use up

growth factors

o Not enough left

to trigger cell

division

� Anchorage dependence

• To divide cells must be

attached to a substrate

Growth Factors and Cancer

• Growth factors influence cell cycle

o Proto-oncogenes

� Normal genes that become

oncogenes (cancer-causing)

when mutated

� Stimulates cell growth

� If switched on can cause cancer

� Example: RAS (activates cyclins)

o Tumor-suppressor genes

� Inhibits cell division

� If switched off can cause cancer

� Example: p53

Cancer & Cell Growth

• Cancer is essentially a failure of cell division control

o Unrestrained, uncontrolled cell growth

• What control is lost?

o Checkpoint stops

o Gene p53 plays a key role in G1 checkpoint

� p53 protein halts cell division if it detects damaged DNA

• Stimulates repair enzymes to fix DNA

• Forces cell into G0 resting stage.

• Keeps cell in G1 arrest.

• Causes apoptosis of damaged cell.

� ALL cancers have to shut down p53 activity.

4

Development of Cancer

• Cancer develops only after a cell experiences ~6 key

mutations (“hits”)

1. Unlimited growth

a. Turn on growth promoter genes

2. Ignore checkpoints

a. Turn off tumor suppressor genes

3. Escape apoptosis

a. Turn off suicide genes

4. Immortality = unlimited divisions

a. Turn on chromosome maintenance genes

5. Promotes blood vessel growth

a. Turn on blood vessel growth genes

6. Overcome anchor & density dependence

a. Turn off touch sensor genes

What causes these “hits”?

• Mutations in cells can be triggered by

o UV radiation

o chemical exposure

o radiation exposure

o heat

o cigarette smoke

o pollution

o age

o genetics

Tumors

• Mass of abnormal cells

o Benign tumor

• Abnormal cells remain at

original site as a lump

• p53 has halted cell

divisions

• Most do not cause serious problems & can be removed by surgery

o Malignant tumors

• Cells leave original site

• Lose attachment to nearby cells

• Carried by blood & lymph system to other tissues

• Start more tumors = metastasis

• Impair functions of organs throughout body

Traditional treatments for cancers

• Treatments target rapidly dividing cells

o High-energy radiation & chemotherapy with toxic drugs

� Kill rapidly dividing cells

o Drugs targeting proteins (enzymes) found only in tumor cells

� Gleevec

• Treatment for adult leukemia (CML) & stomach cancer (GIST)

• 1st successful targeted drug