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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)