Cell Division & Cell Cycle

• http://www.youtube.com/watch?v=Q6ucKWIIFmg

Chapter 12: The Cell Cycle

http://highered.mcgraw-hill.com/olc/dl/120073/bio14.swf

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Omnis cellula e cellulaFrom every cell a cell – Rudolf Virchow

• Cell division: reproduction of cells• Cell cycle: life of a cell from the time it is first

formed from a dividing parent cell until it divides into 2 daughter cells

• Mitosis: nuclear division within a cell, followed by cytokinesis

• Cytokinesis: division of the cytoplasm– It is crucial that genetic material remains the same

from generation to generation

Mitosis• Mitosis functions in– Reproduction of single-celled organisms– Growth– Repair– Regeneration

• In contrast, meiosis produces gametes in sexually-reproducing organisms– Contains half the number of chromosomes of a

somatic cell

Organization of the Genetic Material• Cell division results in genetically

identical daughter cells– This requires DNA replication

followed by division of the nucleus• Genome: genetic content of the cell

– Prokaryotic cells have circular DNACircular DNA: a single long molecule

– Eukaryotic cells contain a number of DNA molecules specific to different speciesOne eukaryotic cell has about 2 meters of DNA

The DNA molecules in a cell are packaged into chromosomes– Eukaryotic chromosomes consist of chromatin, a complex of DNA

and protein that condenses during cell division– Euchromatin: less condensed and readily available for

transcription– Heterochromatin: highly compacted during interphase and

therefore not transcribed• Somatic cells: include all body cells, aside from

reproductive cells• Gametes: reproductive cells, include sperm and egg

Distribution of Chromosomes During Cell Division

• Non-dividing cells contain chromatin– In human cells there are 46 strands of chromatin, or

23 corresponding pairs of strands• Dividing cells contain chromosomes– Chromosomes becomes condensed prior to mitosis– Chomrosomes contain sister chromatids bound by a

centromere• Centromere contains kinetochore• Kinetochore: a structure of proteins associated with

specific sections of chromosomal DNA at the centromere

Chromosome Structure0.5 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

Mitotic Phase Alternates with Interphase in Cell Cycle

• Mitosis: M Phase includes mitosis and cytokinesis– Prophase– Prometaphase– Metaphase– Anaphase– Telophase

• Interphase: 90% of cell cycle; cell grows, producing organelles and proteins– G1: First gap– S: Synthesis, chromosome

replication– G2: Second gap; completes

preparation for cell division

INTERPHASE

G1

S(DNA synthesis)

G2Cyto

kinesis

Mitosis

MITOTIC(M) PHASE

In 24 hours…• Mitosis: 1 hour• G1: 5-6 hours (most variable)• S: 10-12 hours• G2: 4-6 hours

INTERPHASE

G1

S(DNA synthesis)

G2Cyto

kinesis

Mitosis

MITOTIC(M) PHASE

Mitotic Spindle is Necessary for Nuclear Division

• Mitotic spindle: used to segregate sister chromatids in anaphase

• Consists of microtubules and proteins

• Microtubules are able to change in length– Elongate by adding

Tubulin subunits– Shorten by loss of

Tubulin subunits

CentrosomeAster

Sisterchromatids

MetaphasePlate

Kinetochores

Overlappingnonkinetochoremicrotubules

Kinetochores microtubules

Centrosome

ChromosomesMicrotubules0.5 µm

1 µm

Mitotic Spindle• Interphase: the centrosome is

replicated and the two centrosomes remain paired near the nucleus– Centrosome or Microtubule Organizing

Center (MTOC): contains two centrioles• Prophase: spindle formation• Early Prophase: migration of

centrosomes to poles, spindle microtubules grow

• Late Prophase: centrosomes are at the poles, asters form – Aster: radial array of short microtubules– The mitotic spindle includes the

centrosomes, spindle microtubules and asters

Mitotic SpindlePrometaphase:• Kinetochore: protein structure

assiciated with specific sections of the chromosomal DNA at the centromere

• Kinetochore microtubules: attach kinetochore to spindle

• Metaphase Plate: created as microtubules attach to kinetochore, creation indicates Metaphase starts

Cellular Changes Indicate M- Phase Initiation

G2 of Interphase: nuclear envelope intact– Nucleus and nucleolus

present– Centrosome Replication

• Animal cells contain centrioles

– Chromosomes are not condensed and therefore not individually visible

Prophase• Nucleoli disappear• Chromosomes condense• Sister chromatids form– Two genetically identical

arms joined by the centromere and cohesin proteins

– Mitotic spindle forms using microtubules; asters form

– Centrosome migration as microtubules lengthen

Prometaphase

• Nuclear envelope fragments and microtubules invade nuclear area

• Nonkinetochore microtubules elongate

• Chromosomes condense further and gain kinetochore proteins

• Spindle fibers (microtubules) interact with kinetochores

Metaphase

• Longest stage of mitosis– Can last up to 20 minutes

• Metaphase plate: site of chormosome alignment

• Centrosomes are at poles• Sister chromatid

kinetochores attach to kinetochore microtubules

Anaphase• Shortest stage of mitosis• Cohesins between sister chromatids are

cleaved by enzymes– Sister chromatids are now separate

chromosomes• Spindle fibers shorten causing

chromosomes to move to opposite poles– Spindles shorten at kinetochore ends

according to Borisy et al.– Evidenced by Tubulin break down near

fluorescently-labeled kinetochores in pig kidney cells

• Nonkinetochore microtubules elongate cell

Telophase

• Daughter nuclei form in cell• Chromosomes loosen and

become less dense• Nucleoli reappear

Cytokinesis• Occurs in animal cells only• Relies on cleavage marked by a

cleavage currow• Cytoplasmic side of cleavage

furrow contains actin microfilaments and myosin– As the actin and myosin interact

the ring contracts and the cleavage furrow deepens

Cellular Division in Plant Cells• Plant cells form a cell plate following mitosis• Golgi vesicles contain cell wall materials and

migrate toward the center of the cell – forming the cell plate

Binary Fission

• Asexual eukaryotes can utilize mitosis for reproductive purposes – this is called binary fission

• Asexual prokaryotes perform binary fission that does not involve mitosis

Evolution of Mitosis• Some proteins were

highly conserved• In prokaryotes, protein

resembling eukaryotic actin may help with cell division– Tubulin-Like proteins may

help separate daughter cells

Attach to nuclear envelope

Reinforce spatial arrangement of nucleus

Spindle inside nucleus

Cell Cycle Regulation•Cytoplasmic regulators as shown in Mammalian cell Fusion experiment by Johnson and Rao (1970)

Cell Cycle Control System• Control systems vary cell to cell– Skin cells divide frequently, liver

cells only divide when needed (after injury), and nerve and muscle cells never divide

• Cytoplasmic molecules signal cell cycle as shown by Johnson and Rao

• Cell cycle events are regulated cyclicly– These are referred to as Cell

Cycle Checkpoints

Cell Cycle Control Systems• Cell Cycle Checkpoint: control

point in cell cycle where stop and go-ahead signals can regulate the cycle; relies on signal transduction pathways controlled by internal and external molecular signals– G1 checkpoint: acts as a

mammalian restriction point• “Go Signal” permits G1, S, G2 and M

• “Stop signal” causes G0 phase: non-dividing state, state of most human cells

– G2 checkpoint– M checkpoint

Cell Cycle Clock• The rate of cell cycle is

controlled by two proteins:– Cyclins– Cyclin-dependent

kinases (Cdks)

Cell Cycle Clock

• Kinases: activate or inactivate other proteins via phosphorylation– Inactive most of the time– Kinases are activated by cyclins

• Cyclins: regulatory proteins that have a cyclic (fluctuating) concentration in the cell

• Cyclin-dependent kinases (Cdks)– Activity fluctuates with cyclin concentration

Cell Cycle Clock• MPF: maturation-

promoting factor or M-phase promoting factor– MPF is a Cyclin-Cdk complex

• Triggers cell passage from G2 to M

• G2 checkpoint: As cyclin builds during G2 it binds with Cdk– Resulting MPF

phosphorylates proteins, initiating Mitosis

• During anaphase, MPF inhibits itself by destroying its own cyclin– Cdk persists in the cell

Stop and Go Signals

• Internal signals– M Phase checkpoint relies on kinetochore

signaling– Allows for enzymatic cleavage of cohesins

• External factors– Nutrients– Growth Factor Dependency– Density-dependent inhibition– Anchorage dependence

External Factors

• Growth Factor Dependency: over 50 known– Platelet-derived Growth Factor

(PDGF): made by platelets, required for fibroblast division in culture, used at injury sites in animals

– Fibroblasts have PDGF receptors • PDGF receptors are receptor tyrosine

kinases

• Density-Dependent Inhibition: corwded cells stop dividing– Cell surface protein binds the

adjoining cell sends a growth-inhibiting signal to cells

• Anchorage Dependence: cells require a growth substratum

Cancer Cells• Lack response to cell signals– Some can divide indefinitely (ex: HeLa cervical

cancer cells)– Cancer cells are not density or anchorage

dependent• Cancer starts with transformation– Normal cell becomes cancerous; this occurs

regularly and is usually amended by the immune system

– If not, the cancer cell divides and becomes a tumor

Cancer Cells

• Benign tumors: can be removed by surgery• Malignant tumors: invade surrounding tissues and organs, and

often metastasize– Metastasis: spread of cancer to far locations in the body

• Treatment options– Radiation: destroys cancer cells – Chemotherapy: medication that targets rapidly dividing cells (including

cancer cells)• Ex: Taxol – stops dividing cells by prevents microtubule depolymerization in

metaphase, but also affects cells that naturally divide often such as intestinal cells and skin cells of hair follicles