Regulation of the Cell Cycle In Most Animals

Cell Cycle Checkpoints The decision to proceed from one part of the cell cycle to another depends on a variety of factors  Growth  DNA replication  DNA integrity  Cellular integrity  The mechanisms that the cell has to monitor these factors act at “checkpoints”  Generally, the feedback from checkpoints is through negative regulation—sending a signal to stop the progression of the cell cycle rather than dialing back a positive signal.  Schematic of Cell Cycle Checkpoints Schematic of Cell Cycle Checkpoints

Cell Cycle Controls Built-in Clock Affected by chemical messages

3 MAJOR CHECKPOINTS Stop and Go-Ahead Chemical Signals In animals 3 Built-In Stop Signals that must be overridden by Go-Ahead signals G1 - ensures cell is large enough to divide & enough nutrients to support 2 daughter cells G2 - ensures DNA replication is completed successfully M - ensures all chromosomes are attached to spindle fibers by a kinetochore

If criteria at a checkpoint is not met, the cell enters a resting stage (G 0 ). Most cells are in this stage. Muscle & Nerve cells spend virtually all their time in G 0 in adults. G0G0

Built-in Clocks DNA codes for certain proteins to be made in specific cells As proteins accumulate in cells, a critical concentration is reached At this point, the start of the cell cycle is triggered.

CYCLINS Proteins that trigger the cell cycle

Cyclins Accumulate During the G1, S and G2 phases of cell cycle

Cell Cycle Checkpoints Spindle-attachment checkpoint  Before anaphase (separation of chromosomes) there is a checkpoint to ensure the chromatids are correctly attached to the mitotic spindle  The kinetochore (where the chromatids attach to the spindle) is the structure that is monitored  Unattached kinetochores negatively regulate the activity of cdc20- anaphase promoting complex (APC), and anaphase is delayed

cyclin dependent kinase (CDK) Evidence of evolution. CDKs can be taken from one organism and used in another species. Cyclins fit in cyclin dependent kinases, activating the CDK Activated CDKs

Cyclins Four classes  Defined by phase of the cell cycle in which they bind their cdk G1/S phase cyclins-bind cdks at the end of G1, commit cell to DNA replication (cyclin E) S phase cyclins- bind cdks during S phase, required to initiate replication (cyclin A) M phase cyclins- bind cdks immediately before M phase, initiate early mitotic (or meiotic) events (cyclin B) G1 cyclins- involved in progression through the checkpoint in late G1 (cyclin D)

Regulating Molecules Kinases must be activated by another molecule cyclins - protein that activates kinases. Named because its concentration cycles during the cell cycle. Cyclin decomposes after mitosis Kinase - proteins that activate or deactivate other proteins by phosphorylation Kinases give the go-ahead signals for G1 and G2 checkpoints

One type of CDK: mitosis promoting factors (MPF) Works on cell to dissolve nucleus, build spindle fibers... start mitosis

The protein complex must first be phosphorylated by two different kinases: an activating kinase and an inhibitory kinase. A phosphatase must remove the inhibitory phosphate from the M-Cdk to be active. This is essentially the G2/M checkpoint, and mitosis will not occur if the criteria to enter mitosis have not been met.

apoptosis cell suicide - if cells are damaged or too crowded Cells get too crowded, or too high of a density, they are inhibited from G 1 of mitosis If cell had a mutation that caused cyclins to be overproduced, what happens to the rate of mitosis

p53 Mutations at the G1 Checkpoint The gene encoding the p53 tumor suppressor protein is essential for stopping cells with damaged DNA from entering S phase. Mutations in the p53 gene are found in more than 50% of human cancers.p53 gene Many mutations in p53 gene eliminate its ability to activate expression of target genes like the p21 gene. The p21 protein is a cyclin kinase inhibitor (CKI) that inhibits activity of the G1 cyclin-cdk complexes.

Cell Cycle Checkpoints DNA Replication Checkpoint (end of G2)  Cell will not proceed with mitosis if DNA replication is not complete  The way the cell senses this is not understood completely  Cells with mutations in this checkpoint pathway or cultured mammalian cells treated with caffeine will proceed through mitosis with unreplicated DNA. Cells with mutations 1. Cells treated with hydroxyurea did not synthesize DNA. This activated a checkpoint mechanism 2. When caffeine was added, the checkpoint mechanism fails.

Hydroxyurea is used to treat a certain type leukemia, ovarian cancer, melanoma, & certain types of head & neck cancer (including cancer of the mouth, cheek, tongue, throat, tonsils, & sinuses). Hydroxyurea is also used to reduce the frequency of pain & reduce the need for blood trans-fusions in patients with sickle cell anemia. Hydroxyurea treats cancer by slowing or stopping the growth of cancer cells in your body.

mitosis & cancer 100 billion new somatic cells/day in humans. If 1% have a mutation, how many cells would have mutations? Are body (somatic) cells passed on to offspring? Explains why cancers are more common in older (adults) rather than younger people. Compare/contrast benign tumor (neoplasm) and malignant tumor What does it mean when cancer cells have metastasized?