Histology Cell Cycle and Cell Division

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Overview of the Cell Cycle

- G1, S, G2, M, G0

G0 Phase

- nondividing cell or cell population
- inactive cell or cell performing normal functions
- used to include cells in G1, S, G2 because they appear structurally the same
- after mitosis, can choose to go into G0 (differentiate)--some will never divide again (neurons) and some will stay in G0 but divide again later if necessary (hepatocyte)

G1

- pre-replication phase
- variable length of time
- cell prepares for S phase (or differentiates to enter G0 phase)
- 2N

S

- DNA replication ("synthesis") phase
- usually 6-7 hours
- 4N

G2

- post-replication phase
- usually 2-3 hours
- preparation for cell division
- 4N

Karyokinesis

- nuclear division in cells undergoing division
- division of DNA

Cytokinesis

- cytoplasmic division in cells undergoing division

Cancer and the Cell Cycle

- average length of cell cycle for cancer cell is 2-4 days (comparable to cell cycle times for normal cells with high turnover rate such as hemapoietic progenitors and GI mucosal cells)
- suggests cancer is typically a disease of persistant proliferation (rather than rapid proliferation)
- related to aging

Initiating Cell Division

- external stimulation = growth factors (bind to receptors, second messenger system, activate early intermediate gene)

- CYCLIN--increases before cell division (G1); turns on a cdc2+/CDC28 kinase component of maturation promoting factor MPF
- cell division begins with metaphase, cyclin is rapidly degraded after cell division, MPF then decreases

- MPF functions:
1) condense DNA (into chromosomes)
2) spindle apparatus
3) nuclear envelope breakdown (phosphorylation of lamins leads to nuclear breakdown; dephosphorylation of lamins leads to reformation)

- checkpoints

Checkpoints

- cycle is halted temporarily to allow error free completion of the previous phase
- G1--is cell big enough? is environment favorable?
- G2--is all DNA replicated? (plus two G1 questions)
- M--are all chromosomes aligned on spindle?

- if errors noticed, either repaired or cell undergoes apoptosis (see SYLLABUS)

DNA Replication

- semiconservative
- opening the double helix (helicase, helix-destabilizing proteins, DNA topoisomerase)
- replication 5' to 3'
- Okazaki fragments (leading vs lagging, RNA primer, ligase)

Prophase

- disappearance of nucleolus
- dissolution of nuclear envelope (due to phosphorylation of nuclear lamins by MPF)
- chromosomes first appear (microscopical)

Metaphase

- chromosomes line up along equator randomly

Anaphase

- separation of chromatids and centromere
- movement of chromatids to opposite poles (karyokinesis complete)

Telophase

- nuclear envelope reforms
- chromosomes decondense, nucleolus reappears
- completion of cytokinesis

Meiosis

- proceeded by G1, S, G2 phases
- Reduction Division and Maturation Division

SEE SYLLABUS (know pretty well)

Sex Chromosome Pairing

- X and Y not homologous--normal pairing of X and Y in prophase I is made possible due to "pseudoautosomal" regions in X and Y chromosomes
- forms synaptonemal complex between X and Y chromosomes

- sex chromosome aneuploidy often due to nondisjunction of sex chromosomes--Kleinfelter's syndrome (47, XXY) and Turner's Syndrome (45, X)

Lyon Hypothesis

- X-inactivation
- only one X chromosome is active, any extra are inactivated ("heteropyknosis")--randomly chosen early in life, can be seen in nucleus as Barr Body (darkly stained intranuclear mass)
- females--single Barr Body
- males--zero Barr Bodies

Terminating Cell Division

- growth inhibiting factors (e.g. TGF-beta, interferons and TNF) bind to membrane receptors to inhibit cell division
1) decreased cyclin levels
2) spindle (microtubules) function
3) other mechanisms?

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