BIO 300 Lecture3-CellCycle.CancerIntro

BIO 300 Pathophysiology

Cell Cycle

Orderly sequence of events that occur as a cell duplicates its contents & divides.

Cell Cycle

1. Interphase.

a. G₁.

b. S.

c. G₂.

2. M-phase.

a. Mitosis
i. Prophase.

ii. Metaphase.

iii. Anaphase.

iv. Telophase

b. Cytokinesis

G₀

Stage when some cells leave the cell cycle and either remain in an inactive state OR re-enter later.

Interphase

• Typically ~90% of cell cycle time.

• Period of normal cell function; cell prepares for M-phase.

G₁

Characterized by cell growth; protein & RNA synthesis; duplicates organelles/cytoskeletal components; “normal cellular activities.

S

DNA replication (creates 2 copies of DNA – one for each daughter cell that will be formed).

G₂

Continued cell growth/cellular activities & final preparations for cell division (synthesize enzymes/proteins needed for division).

Review of DNA/Chromosomes.....

Recall DNA is a polymer of nucleotides arranged in a double helix.

Chromosome

A long molecule of DNA that is tightly coiled together with several proteins.

Chromosome

• It takes on the organized structure as the cell is dividing (cell division is how we grow from one cell to trillions of cells!).

• DNA wraps around a cluster of histone proteins to form a nucleosome structure.

• Linker DNA holds the nucleosomes together.

• The nucleosomes continue to tighten and supercoil until the chromosome structure is formed.

Sister chromatids

The two arms of a chromosome = identical copies of DNA (one copy for each daughter cell that will be formed).

The Cell Cycle – M-Phase - Prophase

• Spindle begins to form in centrosome area (centrioles are located in this area).

• Chromatin condenses into chromosomes.

• Nucleoli disappear.

• Nuclear envelope dissolves.

The Cell Cycle – M-Phase – Prophase continued...

• Centrosomes/centrioles migrate to opposite poles of cell.

• Spindle spreads across cell.

The Cell Cycle – M-Phase – Prophase continued...

Chromosomes migrate; their kinetochore region attaches to kinetochore microtubules in spindle, allowing them to move.

The Cell Cycle – M-phase - Metaphase

Chromosomes aligned by kinetochore microtubules along equator (aka metaphase plate).

The Cell Cycle – M-Phase - Anaphase

Kinetochore microtubules shorten, pulling sister chromatids apart. (An enzyme called separase is important in this process).

The Cell Cycle- M-Phase - Anaphase continued...

• Chromatids migrate toward centrioles.

• Polar microtubules lengthen, pushing poles apart.

The Cell Cycle- M-Phase - Telophase

• Essentially the opposite of Prophase!

Nuclei reappear.

Spindle disappears.

• By the time telophase ends, cytokinesis has begun!

The Cell Cycle – M phase - Cytokinesis

Actin filaments form a contractile ring along inside of plasma membrane.

End result of cell cycle

2 genetically identical daughter cells.

G1 or Start checkpoint (aka Restriction checkpoint)

• Most crucial.

• Some cells NEVER pass G1 checkpoint.

G2 /M checkpoint

• Often considered most important checkpoint.

• Determines if cell is ready for M-phase (checks to see if DNA replication is complete & without errors).

Meta to Ana checkpoint

• Determines if cell ready for cytokinesis (checks to see if chromosomes aligned properly at equator of cell).

• Triggers separation of sister chromatids.

Cell Cycle Control

• Cell relies upon CDKs & cyclins to pass checkpoints.

• Cyclins.

• CDKs.

Cyclins

• G1 cyclins.

• G1/S phase cyclins.

• S phase cyclins.

• G2/M phase cyclins.

Cyclins

Group of proteins that control progression through cell cycle; activate enzymes called CDKs via phosphorylation.

G1 cyclins- cyclin D binds CDKs; help control the G1/S cyclins

Involved in progression through the checkpoint in late G1 to move into S phase.

G1/S phase cyclins- cyclin E bind CDKs at the end of G1

Commits cell to prepare for DNA replication.

S phase cyclins- cyclin A bind CDKs during S phase =

Required to initiate replication.

G2/M phase cyclins- cyclin B bind CDKs immediately for M phase

Initiate early mitotic events such as spindle formation.

CDKs = Cyclin-dependent kinases

Rnzymes that bind to cyclins.

• Remain in inactive form until bind to cyclin/target protein.

Cell proliferation

Process of increasing cell numbers by mitotic cell divisions.

• Regulated so that the cells produced = cells dying/shed.

• Rate varies among the >200 cell types.

Cell proliferation Example: WBCs & GI cells

Constantly replaced; neurons rarely if ever divide.

Cell differentiation

Detailed process by which proliferating cells become specialized cells.

Cell differentiation

The new cells formed acquire the structure & function of those they are replacing!

Recall that we all begin life as a single-celled zygote

• We then grow by mitosis.

• As we grow, multiple factors affect the differentiation into specific cell types.

• Example: gene expression; stimuli by neighboring cells; nutrients/oxygen.

Apoptosis

A form of programmed cell death.

• Eliminates senescent cells, cells with DNA damage, unwanted cells

Cancer

Disorder of abnormal cell proliferation & differentiation.

Cancer

• Division/growth lacks normal regulatory controls over the cell cycle

• Neoplasm

Tumor

As welling that can be caused by numerous conditions.

2 Classifications:

1. Benign.

2. Malignant.

Anaplasia

Loss of differentiation/characteristics of mature cells.

Pleomorphism

Variation in size & shape of cells (b/c of loss of differentiation).

Pleomorphism

• Nuclei, nucleoli, and chromatin are even abnormal.

• The degree of pleomorphism is used to grade neoplasms on a scale of 1-4.

1 = well-differentiated/minimal anaplasia – 4 =poorly differentiated/marked anaplasia

Genetic instability

• Mutation phenotypes/high rate of mutations in cells.

• Often see aneuploidy, deletions, insertions, point mutations, and amplifications (aka chromosome errors).

Growth factor independence

Can divide without the influence of growth factors (molecules that regulate cell division).

Loss of Cell Density-Dependent Inhibition (aka contact inhibition)

Most cells cease dividing when the population reaches a certain density – not cancer cells!

Loss of Cell Cohesiveness/Adhesion

• Most cells use cadherins to link to/stick to each other & to link intracellularly to the cytoskeleton with the aid of other proteins like catenins.

• Amounts of E-cadherin is reduced in cancer cells.

• ß-catenin accumulates inside cancer cells.

• HYPOTHESIS.

HYPOTHESIS

In the absence of cadherin, the ß-catenin binds to another protein (actinin-4) and that is what shuts off the adhesion process and allows cancer cells to shed/metastasize.

Anchorage dependence

Can remain functional without anchoring to other cells or the extracellular matrix

Cytoskeletal changes

Abnormal cytoskeletal components (actin, intermediate filaments, microtubules).

Characteristics of Malignant Neoplasms

• Antigen expression.

• Unique hormones/enzyme production.

• Life span.

Antigen expression

• Cancer cells express different several surface molecules (antigens).

• They often are like those expressed during embryonic/fetal development instead of mature/differentiated normal cells.

Life span

• Cancer cells are immortal – unlimited divisions so unlimited life span!

• Normal cells have a limited number of divisions before they senesce.

• Telomeres.

Telomeres

Short, repetitive sequences on ends of chromosome arms.

They shorten with each cell division; eventually chromosomes reach a critically short length & can no longer replicate

Loss of cell division ability

Telomerase

Enzyme that prevents telomere shortening; levels are high in cancerous cells.

Telomeres

Molecular structures that cap the ends of chromosomes.

Telomeres

• Often compared to the plastic tips on shoe laces that prevent their unraveling.

• Protect their DNA from damage.

3 pathways:

1. Direct invasion & extension.

2. Seeding of cancer cells in body cavities.

3. Metastatic spread through vascular/lymphatic pathways