12/5/2014. The cell cycle and cell death. The cell cycle: cells duplicate their contents and divide

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1 The cell cycle and cell death The cell cycle: cells duplicate their contents and divide 1

2 The cell cycle may be divided into 4 phases Eucaryotic cell division: Mitosis (nuclear division) Cytokinesis (cell division) 4 2

3 The cell cycle triggers essential processes (DNA replication, mitosis) Cell cycle 1 direction Irreversible Checkpoint Invertebrate egg andxenopus sea urchin, starfish, clam M Only S and M phase no G1 or G2 phase S 6 3

4 Zygote cell division without growth Somatic cells Embryonic cells 7 12 cycles of embryonic cells General somatic cell cycle G1 S G2 M time 8 4

5 Figure 17-5 Molecular Biology of the Cell ( Garland Science 2008) Progression of the cell cycle is regulated by feedback from intracellular events 5

6 Cyclin-dependent protein kinases drive progression through the cell cycle Cyclin-dependent kinases (Cdks) are inactive unless bound to cyclins Active complex phosphorylates downstream targets Cyclin helps to direct Cdks to the target proteins Full activation of the cyclin-cdk complex then occurs when a separate kinase, the Cdkactivating kinase (CAK), phosphorylates an amino acid near the entrance of the Cdk active site Distinct cyclins partner with distinct Cdks to trigger different events of the cell cycle 6

7 4 classes of cyclins G1/S-cyclins S-cyclins M-cyclins G1-cyclins G1/S- Cdk activate Cdks in late G1 trigger progression through Start, commitment to cell-cycle entry Vertebrates Cyclin E Cdk2 Yeast Cln1,2 Cdk1 S-Cdk stimulate chromosome duplication. S-cyclin levels remain elevated until mitosis, control some early mitotic events. Vertebrate Cyclin A Cdk2, Cdk1 Yeast Clb5,6 Cdk1 M-Cdk activate Cdks that stimulate entry into mitosis at the G2/M checkpoint. Vertebrate Cyclin B Cdk1 Yeast Cdk1 G1-Cdk govern the activities of the G1/S cyclins, which control progression through Start in late G1 Vertebrate Cyclin D Cdk4, Cdk6 Yeast Cln3 Cdk1 13 Cyclin levels during the cell cycle Phosphorylation by a protein kinase inhibit cdk activity : i.e. wee vs cdc25 Binding to cdk inhibitor proteins 14 7

8 Cell cycle control is regulated by protein degradation Another cell-cycle control system: SCF Ubiquitylates CKI proteins M-cyclin becomes covalently modified by addition of multiple copies of ubiquitin at the end of mitosis Ubiquitylation mediated by the anaphase promoting complex (APC)/ cyclosome Ubiquitination marks cyclins for destruction by large proteolytic machines called proteasome Multiple mechanism regulate Cdk activity Checkpoints ensure the cell cycle proceeds without errors Figure Molecular Biology of the Cell ( Garland Science 2008) 8

9 S-phase Chromosome Duplication 1 x /cell cycle regulation prereplicative complex and preinitiation complex vs S-Cdk Step 1 Step 2 Figure Molecular Biology of the Cell ( Garland Science 2008) 17 M-Phase Mitosis regulatory Abrupt increase in M-Cdk activity at the G2/M checkpoint triggers early mitosis (prophase, metaphase) APC/C triggers desctruction of securin, liberating a protease that cleaves cohesin initiates separation of the sister chromatids Figure Molecular Biology of the Cell ( Garland Science 2008) 9

10 Mitotic entry is triggered by a steep increase in cyclin B CDK1 activity and both PLK1 and aurora kinase A can contribute to this crucial event Crosstalk between PLK1 and aurora kinase B in the regulation of kinetochore microtubule interactions Emie & Medema, Dephosphorylation activates M-Cdk at the onset of Mitosis 10

11 cohesin condensin Chromosome Dynamics Laboratory Tatsuya Hirano RIKEN Advanced Science Institutewww.asi.riken.jp (Hagstrom & Meyer, 2003) 21 Figure Molecular Biology of the Cell ( Garland Science 2008) 11

12 Checkpoint: spindle assembly Mitosis must not complete unless all the chromosomes are attached to the mitotic spindle Mitotic checkpoint delays metaphase to anaphase transition until all chromosomes are attached Prolonged activation of the checkpoint -->cell death Figure Relation of centrosome duplication to the cell cycle. 12

13 Molecular Biology of the Cell ( Garland Science 2008) Control of cell division and cell growth Mitogens, stimulate cell division, primarily by triggering a wave of G1/S-Cdk activity that relieves intracellular negative controls that otherwise block progress through the cell cycle. Growth factors, stimulate cell growth (an increase in cell mass) by promoting the synthesis of proteins and other macromolecules and by inhibiting their degradation. survival factors, promote cell survival by suppressing the form of programmed cell death known as apoptosis. Figure Molecular Biology of the Cell ( Garland Science 2008) 13

14 Figure Molecular Biology of the Cell ( Garland Science 2008) Limitation cell number and cell cycle arrest Limitation cell number Replicative cell senescence Abnormal proliferation signals cause cell cycle arrest 28 14

15 Checkpoint: DNA damage arrests the cell cycle in G 1 Cells can withdraw from the cell cycle and dismantle the regulatory machinery G 0 is a quiescent state Cdks and cyclins disappear Some cells enter G 0 temporarily and divide infrequenty (I.e. hepatocytes) Other differentiated cell types (neurons) spend their life in G 0 15

16 CELL DEATH 31 Apoptosis vs. necrosis Necrotic cell Apoptotic cells 16

17 Apoptosis 33 Melino et al.2005 Different types of programmed cell death. Morphologically distinct types of cell death. At least 11 different types of cell death are known, 10 of which procede according to genetically programmed mechanisms. Some forms of death are not considered separately since they are identical to those indicated, that is, oncosis is a form of necrosis, and anoikis is apoptosis triggered by cell detachment. This does not exclude the possibility of additional mechanisms in higher or lower organisms such as in bacteria and Dictyostelium. The columns indicate, in a very simplified and schematic way, the different characteristics of the different forms of death, and in particular the findings in the plasma membrane, the nucleus, the mitochondria, and other cytosolic organelles. The details are only indicative, and are presented especially to highlight the differences between apoptosis, autophagy and cornification (boxes), which are discussed in detail in this special issue of Cell Death Differentiation. WD, Wallerian degeneration; PLT, platelets; TG, 34 transglutaminases; NO, nitric oxide; NCX, sodium calcium exchange channel; IAP, inhibitor of apoptosis proteins 17

18 Pathogen-induced host cell death. 35 Apoptosis: the necessity for cell death in multicellular organisms Embryonic morphogenesis Killing by immune effector cells Wiring of the developing nervous system Regulation of cell viability by hormones and growth factors (most cells die if they fail to receive survival signals from other cells) 18

19 Developmentally-regulated apoptosis Apoptosis: regulation of apoptosis 38 19

20 Figure 1. Cell death outcomes following fungal pathogen attack. Dickman MB, de Figueiredo P (2013) Death Be Not Proud Cell Death Control in Plant Fungal Interactions. PLoS Pathog 9(9): e doi: /journal.ppat Cell death modalities in response to infection. Diagram representing some of the characteristic features of different types of programmed cell death that can occur in response to infection in plants and mammals. HR cell death in plants (a) and pyroptosis (b) and Necroptosis (c) in mammalian cells. See the text for details Coll, P Epple and J L Dangl,