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Control Points in the Mitotic Cell Cycle Control at the G2/M Transition DNA Replication Control at the G1/S Transition Control Points in the Mitotic Cell Cycle Positive Control by Cyclin/Cdk Negative Control By p53 (checkpoint) Cyclin Protein Levels Vary During the Cell Cycle Cyclin/Cdk Complexes During the Cell Cycle Expression of M-cyclin Gene Ubiquitin-dependent proteolysis Ubiquitin-dependent proteolysis Expression of S-cyclin Gene Cyclin/Cdk Phosphorylates Rb Protein (RTK) (Ras-MAP Kinase) Activation of “S-Phase Genes” Cell Cycle Checkpoints Control Points in the Mitotic Cell Cycle Positive Control by Cyclin/Cdk Checkpoint by p53 The p53 Cell Cycle Checkpoint or Short Telomeres (ATM Kinase) The p53 Cell Cycle Checkpoint or Short Telomeres (ATM Kinase) DNA Repair System Programmed Cell Death Connection to Cancer RTK/Ras pathway HER2 gene amplifications Ras Checkpoint pathway p53 ATM Kinase Normal Ras and Oncogenic Ras Normal Ras Oncogenic Ras Connection to Cancer RTK/Ras pathway HER2 gene amplifications Ras Checkpoint pathway p53 ATM Kinase p53 Domain Structure Cyclin/Cdk Complexes During the Cell Cycle Expression of M-cyclin Gene Ubiquitin-dependent proteolysis Ubiquitin-dependent proteolysis Expression of S-cyclin Gene Cyclin/Cdk Phosphorylates Nuclear Lamins M-Cyclin/Cdk Cyclin/Cdk Phosphorylates APC P M-Cyclin/Cdk Cell Cycle Checkpoints Cyclin/Cdk Complexes During the Cell Cycle Expression of M-cyclin Gene Ubiquitin-dependent proteolysis Ubiquitin-dependent proteolysis Expression of S-cyclin Gene Necrosis and Apoptosis Loss of Homeostasis Membrane rupture Release of cellular contents (no inflammation) Normal Cell Apoptotic Cell Apoptosis (Programmed Cell Death) Regulated Response to: Extra-cellular “death” signaling molecules DNA Damage Apoptosis (Programmed Cell Death) ~ 50% of nerve cells are eliminated by apoptosis during development Sculpting of digits “Self-reactive” T- cells are eliminated by apoptosis Protect organism from mutations Aging Mitochondrion Apoptotic Receptors and Signal Molecules “Death” Receptor “Death” Signaling Molecules TNF FasL TRAIL Bax Disruption of Phospholipid bilayer Release of Cytochrome C from Mitochondria Pg. 628 Caspase Activation Pg. 627 Caspase Cascade Pg. 627 Apoptosis -- Links to Disease Many types of cancer cells are “apoptosis resistant” Apoptosis resistance in autoimmune diseases Overactive neuronal apoptosis in Alzheimer’s and Parkinson’s Thalidomide induces apoptosis Stem Cell Concept Signal Molecules Signal Molecules Commitment and Differentiation Pg. 721 Stem Cell Concept Pluripotent Multipotent M-Phase Cdk Activity Egg Cell and Sperm Cells Pg. 661 M-Phase Cdk Activity 8-cell Embryo (pre-compaction) Blastocycst Uterus Inner Cell Mass (ICM) Blastocyst Blastocoel Trophoblast 50 µm Preimplantation Development (~ 7 days) (~ 9 weeks) In Vitro Fertilization (IVF) Sperm cells Embryos (4-cell stage) Isolation of ICM Cells Pluripotent Embryonic Stem Cells Signal A Signal B Signal C IVF “Stem Cell Line” Signal D Signal E Pg. 724 Colony of Human Embryonic Stem Cells Stem Cells Mouse “feeder” cells Teratomas Neural epithelia Bone Retinal epithelia Cartilage Pluripotent Embryonic Stem Cells Signal A Signal B Signal C IVF “Stem Cell Line” Signal D Signal E Pg. 724 Stem Cell Therapy Somatic Cell Nuclear Transfer “Donor” Reconstructed Zygote “enucleated egg” Pg. 725 Science 318: 1917-1920 December 21, 2007 Nature 456: 344-349 November 20, 2008 Tissues with Adult Stem Cells Bone marrow/peripheral blood/umbilical cord Blood vessels Brain/spinal cord Skeletal muscle Colon Liver Pancreas Retina/cornea Skin Dental pulp Adult Stem Cell Life-long Multipotent Stem Cell Niche Stem Cell Signals for self-renewal (Common Myeloid progenitor) (Common Lymphoid progenitor)