Notes

The Cell Cycle:
Cells divide to: increase number of somatic cells for growth and development, production of gametes in sexual production, asexual reproduction, and to replace cells lost through apoptosis.
Events of the cell cycle: DNA replication, mitosis, cytokinesis
G1 - cellular contents, excluding chromosomes are duplicated
S - Each of the 46 chromosomes is duplicated by the cell
G2 - cell double checks duplicated chromosomes for errors and makes repairs
Mitosis- division of chromosomes
Cytokinesis - creation of 2 new daughter cells
RBCs do not divide and are instead replaced by differentiation. Lack centrioles that are essential for cell division, 2-3 million replaced per second
S-Phase:
Human somatic cells have 46 chromosomes (23 pairs). 22 autosomes, X and Y. They are diploid meaning they have two copies of the genome. Human sperm and egg cells have 23 chromosomes and are haploid (one copy). Immediately after DNA replication a human somatic cells will have 46 double chromosomes (4N=92). During mitosis the double chromosomes are split to produce 92 single chromosomes half of which go to each daughter cell.
M-Phase:
Chromosomes line up in the middle of cell. Spindles attach to chromosomes pulling them apart. Astral tubules balances the cell, kinetochore microtubules capture duplicated chromosomes. Prior to mitosis, each chromosome makes a copy of itself and then thicken and coil. In early prophase the centrioles, which have divides form asters and move apart. The nuclear envelope disappears. In the late prophase centrioles and asters are at opposite poles. The double chromosomes with their centromeres attached to spindle fibers line up in the middle of the cell. In early anaphase the centromeres have split in half and chromosomes move to opposite poles. In late anapahse, the chromosomes have almost reached their respective poles and the cell membrane pinches at the center. The cell membrane completes constriction in telophase. Nuclear membranes form around the chromosomes. At mitosis completions there are two cells with the same number of chromosomes as their parent cells.
Cyclin and cyclin-dependent kinase: Drive progression through cycle
Cdks are inactive unless bound to cyclin. CDK-cyclin active complex phosphorylates down stream targets. Cyclin directs Cdk to target proteins. Complex is comprised of two lobes with the active site located in the cleft between large and small lobes. ATP fits into cleft. Enzyme catalyzes the transfer of gamma-phosphate from ATPto hydroxyl group of serine, threonine, or tyrosine amino acid of substrate. Phosphate group of phosphoprotein reacts -OH group of a Ser, Thr, or Tyr.
Cyclins and Cdks partner to trigger cell cycle progression
- G2: CDK1-cyclin A
- M: CDK1- cyclin B
- G1: CDK4/6 - cyclin D
- G1/S: CDK2 - cyclin E
- S: CDK2 - cyclin A
- Cyclin dependent kinase inhibitors regulate progression
Retinoblastoma controls entry into S-phase:
E2F transcription factor controls expression of genes requires for S phase. Unphosphorylated Rb binds to E2F preventing transcription. Cell growth triggers phosphorylation of Rb so E2F can bind.
S-phase entry in animal cells. E2F encodes proteins required for S-phase entry. E2F function controlled by Rb. During G1, Rb binds to E2F and blocks the transcription of S-phase genes. Cells are stimulated to divide by extracellular signals, active G1-CDK accumulates and phosphorylates Rb, reducing affinity for E2F. Rb disassociates, allowing E2F to active S-phase gene expression. Positive feedback loop. CDK2-cyclin E are positive regulators of S-phase entry, while p27,p21, and p16 are negative. CDK inhibitors block G1 and S phase.
M-Cdk activation
-Cyclin binding (CDK1- cyclin B)
- CDK-activating phosphorylation (CAK)
- Inhibitory phosphroylation (Wee 1)
- Removal of inhibitory phosphate (p-Cdc25)
Mitogens stimulates proliferation by inhibition of Retinoblastoma protein via signalling cascade when it binds to its receptor.
Plate-derived growth factor regulates cell growth and division. Released by platelets to active macrophages and endothelial cells. Binds to receptor tyrosine kinase triggering a signal cascade that results in phosphorylation of Rb.
Retinoblastoma: mutation of RB1 tumor suppressor gene causing tumor in the eye. Autosomal recessive