Regulation of cell cycle. Dr. SARRAY Sameh, Ph.D

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1 Regulation of cell cycle Dr. SARRAY Sameh, Ph.D

2 Control of cell cycle: Checkpoints Are the cell cycle controls mechanisms in eukaryotic cells. These checkpoints verify whether the processes at each phase of cell cycle have been accurately completed before progression to the next phase. There are 3 main checkpoints: G1/S cell cycle checkpoint: presents at the end of the G1 phase. It helps in taking decision of whether the cell should divide, delay division or enter a resting stage (G0). G2/M: DNA damage checkpoint : located at the end of G2 phase. It prevents the cell from entering mitosis (M phase) if the genome is damaged. It also checks if the cell is big enough (i.e. has the resources to undergo mitosis) M (Metaphasis) checkpoint: occurs in metaphase. It is also called spindle check point. It checks whether all the chromosomes are properly attached to the spindle or not. It governs the alignment of the chromosomes. If there are mistakes then it delays the cell in entering into anaphase. How do they do that?

3 Cell cycle regulation Cell cycle regulators (proteins & enzymes) control cell cycle progression: * Cyclins (proteins) * Cyclin dependent KINASES (Cdks) (enzymes)

4 Cyclins - Are family of proteins that controls the progression of cells through the cell cycle by activating CDKs enzymes. - Level fluctuate: cyclin concentrations rise and fall at specific times in the cell cycle -There are several types of cyclins that are active in different parts of the cell cycle. -There are 2 main groups: G1/S cyclins: cyclin A, D and E G2/M cyclins: cyclin B

5 Cyclin-dependent kinases: CDKs CDKs are activated by cyclin binding. CDK expression is constant during the cell cycle Although their expression is constant, their enzymatic activities fluctuates, depending on the availability of the cyclins required for their activation. Some cyclins form complexes with certain CDK to stimulate their kinase activity: The CDK itself is phosphorylated, then, the cyclin-cdk complex phosphorylate key proteins on Ser & Thr residues leading to a change in the activity of the key proteins Such changes for the regulatory proteins allows initiation of the next phase: Exemples: - Active CDK2, activate target proteins involved in the transition phase (G1 to S) and for initiation of DNA synthesis. - Active CDK1, activate target proteins critical for initiation of mitosis (M phase)

6 Cyclin-dependent kinase inhibitors (CDKIs) The complex (cyclin-cdk) can be inhibited by protein called cyclin-dependent kinases inhibitor (CKI). Cell cycle progression is negatively controlled by CDKIs.

7 Positive regulators vs Negative regulators Positive regulators are those which control the changes necessary for cell division: Cyclins Cyclin Dependent Kinases Negative regulators are those which controls the positive regulators. They include: Tumor suppressor proteins: function in various way to inhibit the progression through the cell cycle: Rb proteins & P53 proteins Inhibitors of CDKs (CDKIs)

8 Retinoblastoma (Rb) protein -The product of the tumor suppressor gene, RB. - Loss of function, mutations in RB are associated with the disease retinoblastoma (malignant tumor of retina, a rare childhood tumor). - The Rb protein function is determined by its phosphorylation status: Phosphorylation of Rb protein by G1 cyclin-cdk complex at multiples sites, prevents its association with transcripion factor, thereby permitting to activate transcription of genes required for entry into S phase.

9 2- p53 protein: Produced by the p53 gene (guardian of the genome) 50% of human cancer show p53 mutation p53 protein prevent cancer because: it can arrest growth by holding the cell cycle at G1/S regulation point on DNA damage. It can activate DNA repair proteins when DNA is damaged Activate apoptosis when the DNA damage is irreparable

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