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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 - PowerPoint PPT Presentation
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Control Points in the Mitotic Cell Cycle
DNAReplication
Control at the G1/S Transition
Control at the G2/M Transition
Control Points in the Mitotic Cell Cycle
Positive Control byCyclin/Cdk
Negative Control By p53 (checkpoint)
Cyclin Protein Levels Vary During the Cell Cycle
Cyclin/Cdk Complexes During the Cell Cycle
Expression ofM-cyclin Gene
Expression ofS-cyclin Gene
Ubiquitin-dependentproteolysis
Ubiquitin-dependentproteolysis
(RTK)
(Ras-MAP Kinase)
Activation of “S-Phase Genes”
Cyclin/Cdk Phosphorylates Rb Protein
Cell Cycle Checkpoints
Control Points in the Mitotic Cell Cycle
Positive Control byCyclin/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
Checkpoint pathway
HER2 gene amplificationsRas
p53ATM Kinase
Normal Ras and Oncogenic Ras
Normal Ras Oncogenic Ras
Connection to Cancer
RTK/Ras pathway
Checkpoint pathway
HER2 gene amplificationsRas
p53ATM Kinase
p53 Domain Structure
Cyclin/Cdk Complexes During the Cell Cycle
Expression ofM-cyclin Gene
Expression ofS-cyclin Gene
Ubiquitin-dependentproteolysis
Ubiquitin-dependentproteolysis
Cyclin/Cdk Phosphorylates Nuclear Lamins
M-Cyclin/Cdk
Cyclin/Cdk Phosphorylates APC
M-Cyclin/Cdk
P
Cell Cycle Checkpoints
Cyclin/Cdk Complexes During the Cell Cycle
Expression ofM-cyclin Gene
Expression ofS-cyclin Gene
Ubiquitin-dependentproteolysis
Ubiquitin-dependentproteolysis
(no inflammation)
Loss of HomeostasisMembrane ruptureRelease of cellular contents
Necrosis and Apoptosis
NormalCell
Apoptotic Cell
Regulated Response to:
Extra-cellular “death” signaling molecules
Apoptosis (Programmed Cell Death)
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
Aging
Protect organism from mutations
Mitochondrion
Apoptotic Receptors and Signal Molecules
“Death” Signaling Molecules
TNFFasLTRAIL
“Death” Receptor
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
Thalidomide induces apoptosis
Overactive neuronal apoptosis in Alzheimer’s and Parkinson’s
Stem Cell Concept
Signal Molecules
Pg. 721
Signal Molecules
Commitment andDifferentiation
Stem Cell Concept
PluripotentMultipotent
M-Phase Cdk Activity
Egg Cell and Sperm Cells
Pg. 661
M-Phase Cdk Activity
8-cell Embryo (pre-compaction)
Blastocycst
Uterus
BlastocystInner Cell Mass (ICM)
50 µmTrophoblast
Blastocoel
Preimplantation Development (~ 7 days)
(~ 9 weeks)
In Vitro Fertilization (IVF)
Sperm cells
Embryos (4-cell stage)
Isolation of ICM Cells
Pluripotent Embryonic Stem Cells
Pg. 724
Signal E
Signal D
Signal C
Signal B
Signal A
IVF
“Stem Cell Line”
Colony of Human Embryonic Stem Cells
Stem Cells
Mouse“feeder”cells
Teratomas
Neural epithelia
Retinalepithelia
Bone Cartilage
Pluripotent Embryonic Stem Cells
Pg. 724
Signal E
Signal D
Signal C
Signal B
Signal A
IVF
“Stem Cell Line”
Stem Cell Therapy
Pg. 725
“enucleated egg”
“Donor”
Somatic Cell Nuclear Transfer
ReconstructedZygote
Science 318: 1917-1920December 21, 2007
Nature 456: 344-349November 20, 2008
Tissues with Adult Stem Cells
Bone marrow/peripheral blood/umbilical cordBlood vesselsBrain/spinal cordSkeletal muscleColonLiverPancreasRetina/corneaSkinDental pulp
Adult Stem Cell
Multipotent
Life-long
Stem Cell Niche
Stem Cell
Signals for self-renewal
(Common Lymphoid progenitor)
(Common Myeloid progenitor)
