The Cell Cycle PDF

The Cell Cycle Prof. Corrado Santocanale Molecular Medicine Centre for Chromosome Biology Bioscence building [email protected] www.santocanalelab.net • Cell cycle overview • • Main events occurring Phases of cell cycle • Cyclin dependent kinases (CDKs) • CDK regulation • Chromoso...

The Cell Cycle Prof. Corrado Santocanale Molecular Medicine Centre for Chromosome Biology Bioscence building [email protected] www.santocanalelab.net • Cell cycle overview • • Main events occurring Phases of cell cycle • Cyclin dependent kinases (CDKs) • CDK regulation • Chromosome replication • DNA replication • Centrosome duplication • Regulation of the Cell Cycle • Checkpoints 2 Overview • In order for adult multicellular organisms to develop from a single fertilized egg, cell growth and division has to occur at the appropriate times and in the appropriate places • In order for a tumor to growth cell division occur at the inappropriate times and in the inappropriate places Tasks • Cells must accomplish two basic things during the cell cycle: – Copying cellular components – Dividing the cell so that components are distributed evenly to the daughter cells • The alternating “growth” and “division” activities of the cell is called the “cell cycle”. • The division activity corresponds to “M phase”. • The “growth” activity corresponds to “Interphase”. Growth and division of cancer cells under the microscope Figure 17-4 Molecular Biology of the Cell (© Garland Science 2008) Cell cycle timing Varies between cells depending on function and origin Cell cycle timing Varies between cells depending on function and origin Interphase: G1 • Events during G1 – Cell growth – Preparation of chromosomes for replication – Duplication of cellular components – G1 checkpoint (or restriction point); cell commits to division or exits from cell cycle Interphase: S phase • DNA replication – All chromosome are duplicates • Duplication of the centrosome – The centrosome is located near the nucleus of the cell and contains the microtubule organizing center MTOC in animal cells. It contains two centrioles that migrate to the poles before cell division and serve to organize the spindle. Interphase: G2 • Cell growth • Checkpoint (restriction point) for entry into M phase M phase • Cell division (mitosis) • Can be subdivided into six sub-phases: – Prophase – Prometaphase – Metaphase – Anaphase – Telophase – Cytokinesis Phases of mitosis: prophase • Chromosomes begin to condense. – Requires condensin and DNA topoisomerase II. • The (duplicated) centrosomes separate. • Histones undergo mitosisspecific modifications Prophase (from Rieder lab webpage) Phases of mitosis: prometaphase • Microtubules from opposite spindle poles (centrosomes) bind chromosomes at kinetochores to initiate bipolar orientation • Nuclear envelope breakdown occurs Early Late Prometaphases (from Rieder lab webpage) Phases of mitosis: metaphase • All chromosomes have made bipolar attachments to spindle poles. • Chromosomes align at the metaphase plate. EM Light Metaphase (from Rieder lab webpage) Phases of mitosis: anaphase • Chromatids separate and move toward the opposite spindle poles; poles separate • Metaphase - anaphase transition is tightly regulated! • Nuclear envelope reassembly commences. Early Late Anaphases (from Rieder lab webpage) Phases of mitosis: telophase • Nuclear envelope reassembles around sister chromatids • Poleward movement of chromosomes continues. • Cleavage plane is specified Early Phases of mitosis: cytokinesis • Separation of daughter cells • Formation of the cleavage furrow by a contractile ring of actin filaments. • Chromosomes decondense and nuclear structures reform. Early Late Late Cell cycle phases under the microscope Cyclin dependent kinases control the Cell Cycle • Kinases • Cyclin dependent kinases • Cyclins: – Enzymes that phosphorylate other proteins – Catalyic domain – Cdk levels are constant – Cdks must bind to cyclins to be activated – Proteins whose levels rise and fall during the various phases of the cell cycle (primary regulators of the cyclindependent kinases) – Interact with the cyclin-dependent kinases (cdk) • The complexes of cyclin+cdk act in concert – Cdks phosphorylate proteins that initiate or regulate cell cycle activities. Figure 17-16 Molecular Biology of the Cell (© Garland Science 2008) Multiple Cdks and Cyclins regulate passage of mammalian cells through the cell cycle • G1 phase • • Cyclin D Cdk4; Cyclin D Cdk6 Cyclin E Cdk2 • S phase • • Cyclin E Cdk2 Cyclin A Cdk2 • G2 phase • • Cyclin A Cdk2 Cyclin A Cdk1 • Mitosis • • Cyclin A Cdk1 Cyclin B Cdk1 (MPF; mitosis promoting factor) Activation of CDKs • • Cyclin binding Phosphorylation of activation loop by CDK activating kinases (CAKs) Figure 17-17 Molecular Biology of the Cell (© Garland Science 2008) Inhibition of CDKs • Inhibitory phosphorylation by Wee kinases – Removed by CDC25 phosphatases Figure 17-18 Molecular Biology of the Cell (© Garland Science 2008) Inhibition of CDKs • By binging of Cyclin dependent kinases inhibitor (CDKIs) – Small proteins – Important tumor suppressors Control of cyclin by ubiquitin mediated degradation Figure 17-20a Molecular Biology of the Cell (© Garland Science 2008) Reading • The Cell Cycle, in Molecular Biology of the CellAlberts et al - Chap 17 (5th edition) • Cell cycle control in cancer. Matthews HK, Bertoli C, de Bruin RAM. Nat Rev Mol Cell Biol. 2022, vol 23, pag 74-88