Cell Cycle and its Regulation PDF

Cell Cycle and its Regulation Dr. Sarray Sameh Ph.D Department of Medical Biochemistry  Cell Cycle ◼ The series of events that take place in eukaryotic cells leading to its replication. ◼ The cell cycle is broadly divided in two stages: ◼...

Cell Cycle and its Regulation Dr. Sarray Sameh Ph.D Department of Medical Biochemistry  Cell Cycle ◼ The series of events that take place in eukaryotic cells leading to its replication. ◼ The cell cycle is broadly divided in two stages: ◼ Interphase (I) stage: characterized by: ◼ Cellular growth, ◼ Accumulation of nutrients needed for mitosis and ◼ DNA replication ◼ Mitotic (M) phase: the cell splits itself into two distinct cells, referred to also as "daughter cells".  Interphase of the cell cycle ◼ Most cell growth and nuclear activities take place. ◼ Interphase consists of 4 phases: G1, S, G2 and G0 ◼ G1-phase ▪ The first phase within interphase ,between mitosis and S phase. ▪ Variable duration, even among different cells of the same species. ▪ Characterized by high rate of cellular biosynthetic activities and synthesis of various enzymes required in S phase, especially those needed for DNA replication.  Interphase of the cell cycle ▪ S-phase ▪ The period during which DNA replication occurs ▪ Two genetically identical sister chromatids are produced from each chromosome; and are held together at the centromere ▪ G2-phase. ▪ The period between S phase and mitosis. ▪ Associated with rapid control of replicated DNA and preparation for division. Mitosis Phase ◼ Relatively brief ◼ Consists of: ◼ Nuclear division: karyokinesis ◼ Cytoplasmic division: cytokinesis. ◼ Broken down into several distinct phases: ◼ Prophase: the nucleolus fades, chromatin condenses into chromosomes. ◼ Prometaphase: break down of nuclear envelope ◼ Metaphase: alignment of all chromosomes at the metaphase plate ◼ Anaphase: daughter chromosomes are pulled apart and move to the cell poles ◼ Telophase: daughter chromosomes are at the poles; the spindle fibers disappear. ◼ cytokinesis: cytoplasm divides, parent cells becomes 2 daughter cells with identical genetic information Exit Phases: G0-phase & Meiosis ◼ Cells can leave the cell cycle at the G1 to transit to G0 phase ◼ G0 phase; A non-dividing (rest) state, associated with variable level of differentiation.: ◼ Some cells may keep the ability to further differentiate, while others undergo no further differentiation (muscle and nerve cells). ▪ Germinal cells by entering meiosis: Replaces mitosis in the cell cycle, Important for introducing genetic variation.  Control of cell cycle: Checkpoints Checkpoints is a stage in the eukaryotic cell cycle at which the cell examines internal and external cues and decides whether to move forward with division or not. There are 3 main checkpoints: G1 checkpoint: It verifies the integrity of DNA during the late G1 phase before proceeding to the S phase and DNA replication. G2 checkpoint verifies the completeness of genomic DNA replication before committing to mitosis. M (Metaphase) checkpoint: it monitors the attachment of chromosomes to the mitotic spindle before proceeding into anaphase and How do they chromosomal segregation. do that?  Cell cycle regulators Network of regulatory proteins: monitor and dictate the progression of the cell through the different stages of the cell cycle Positive regulators are those which control the changes necessary for cell division: they include Cyclins Cyclin Dependent Kinases (Cdks) Negative regulators are those which controls the positive regulators. They include: Tumor suppressor proteins: Rb proteins & P53 proteins. Inhibitors of Cdks (CDKIs) which are 2 types: Ink family (inhibitors of kinases) CIP family (CDKs inhibitory proteins)  Positive Regulators: Cyclins and cyclin- dependent kinases (CDKs) 1- Cyclins: ▪ 4 basic types: G1 cyclins, G1/S cyclins, S cyclins and M cyclins ▪ Each cyclin is associated with a particular phase, transition, or set of phases in the cell cycle (M cyclin for example peaks at the transition from G2 to M phase ) ▪ Cyclin drive the events of cell cycle by partnering with a family of enzymes called cyclin dependent kinases (CDKs) forming a heterodimer protein kinase. 2. Cyclin dependent kinases (CDKs) ▪Family of proteins kinase that regulate the cell cycle ▪Alone, CDK is inactive, but binding of cyclins to Cdks causes activation of their kinase activity, making them functional enzymes and allowing them to modify the target proteins ▪The attached phosphate group acts like a switch making this target proteins more or less active ▪The levels of CDKs are constant throughout the cell cycle but CDK activity and target proteins change as levels of various cyclins rise and fall during the cell cycle. ▪There are multiple cyclins and Cdks in eukaryotic cells. Each cyclin can complex with more than one Cdk and each CDK may interact with more than one cyclin.  Cyclin-CDK complex activity during the cell cycle ▪The activity of different cyclin-CDK complexes oscillate through the cell cycle Cyclin class Function Cyclin-CDK complex(es) G1 cyclin Helps the passage of cells through the check point in Cyclin D-CDK4 (cyclin D) late G1 phase Cyclin D-CDK6 G1/S cyclin (E) Helps the cells at the end of G1 phase to commit to Cyclin E-CDK2 DNA replication and enter S phase S cyclin (A) Necessary for the initiation of DNA synthesis Cyclin A-CDK2 M cyclins Passage to M phase; Necessary for the nuclear division Cyclin A-CDK1 (A & B) during mitosis Cyclin B-CDK1 (MPF)  Maturation promoting Factor MPF ◼ These proteins are located in the nuclear envelope; the phosphorylation results: ◼ In nuclear envelope breakdown and ◼ Activation of targets that promote chromosome condensation ▪ In addition, MPF triggers its own destruction by activation of Anaphase promoting complex/cyclosome (APC/C), a protein complex that causes: ▪ B cyclins to be destroyed starting in Anaphase. ▪ Destruction of proteins that hold the sister chromatid together allowing them to separate in anaphase.  Negative regulators ▪Tumor suppressor proteins ▪CDK inhibitors: 2 families ▪CIP (CDK interacting protein)or /KIP: Kinase inhibitory protein The CIP/KIP family is made up of three proteins: p21, p27, p57. Their activity primarily involves the binding and inhibition of CDK2-cyclin E and CDK2-cyclin A; ▪Ink: Inhibitor kinase family The Ink family: The members of this family (p15, p16, p18, p19): Their activity primarily involves the binding and inhibition of G1 cyclin (cyclinD)-CDK4/CDK6; which halt the cycle in G1 phase Tumor suppressor proteins Prevent uncontrolled growth  Rb gene: Governor of the cell cycle ▪ Rb gene regulate the advancement of cells from G1/S phase of cell cycle. ▪pRb arrests the cell cycle at the G1 phase of the cell cycle ▪If Rb gene is mutated it encodes to mutated Rb protein unable to halt the cycle in G1 phase leading to cancer of retina (retinoblastoma)  Rb regulation ▪The active form of Rb is hypo phosphorylated It associates with E2F family proteins and Inhibits E2F‐dependent activation of genes that stimulate the entry into S phase and halt the cell cycle advancement. ▪In active cycling cells, ▪ Rb is progressively hyperphosphorylated: ▪ hyperphosphorylated Rb cannot inhibit E2F ▪ E2F binds DNA and activates genes whose products are important for S phase. 2- p53 gene: Guardian of the genome It prevents the propagation of genetically damaged cells. Can be activated by hypoxia, inappropriate oncogene signaling or DNA damage. The activated p53 controls the expression of genes involved in cell cycle arrest, DNA repair, cellular senescence and apoptosis. p53 protein prevent cancer : Activated p53 stimulates CKI gene which produce p21 protein which holds the cell cycle at G1/S phase to allow DNA repair If the damage is irreparable, p53 triggers apoptosis END!