Transcript Extracellular Regulation of the Cell Cycle by Signal Transduction

Intracellular Regulation of Cell Cycle & Apoptosis
Negative regulation of cell cycle by intracellular signals
Checkpoint
p21 inhibits
cdk2-cyclinA
p53 detects DNA damage &
activates p21
Checkpoints: block cell from proceeding through cell cycle if cell is damaged.
Positive Regulation of Cell Cycle
Kinase Cascade:
Other signals induce phosphorylation of certain kinases.
These kinases phosphorylate other kinases, activating them, etc.
Eventually, phosphorylate certain TFs, activating them.
Express genes needed to progress through cell cycle.
Positive Regulation of Apoptosis
Damaged mitochondria
leak mitochondria proteins into cytoplasm.
Ex: cytochrome c binds to Apaf (Apoptosis Pathway Activating Factor)
Apaf-cytochrome c activates initiator caspase
Negative Regulation of Apoptosis
Bcl-2 inhibits activity of Apaf:
Possibly involves:
(a) Binding to Apaf
(b) Prevent mitochondria from releasing cyto. c
Extracellular Regulation of the Cell Cycle by
Signal Transduction
Peptide Hormones
(e.g., Insulin)
Bind to cell surface
receptors & activate
them
Growth Factors
Receptor Tyrosine Kinase (RTK)
Transmembrane proteins
Growth Factor (Ligand) binds to
extracellular domain of receptor protein
Plasma membrane
Activates cytoplasmic domain (kinase)
Growth Factor
Ligand binding activates RTK
Direct phosphorylation of target proteins
& activation of kinase cascade
Activated RTK
Activated RTK activates adapter protein
G-protein-mediated signal
transduction pathway
Activated Adapter protein
activates Sos protein
Activated Sos activates a
G protein (e.g., Ras)
G-proteins
Active when bound to GTP
Inactive when bound to GDP
GTP
GDP
Activated Ras activates Raf.
This activates kinase cascade.
Activates TFs, leading to
changes in txn of target genes.
Classes of Growth Factors
Mitogens
stimulate cell division
Ex: Epidermal Growth Factor (EGF)
Activates signal transduction pathway that
promotes cell division.
Inhibitors of cell division
Activate signal transduction pathways that inhibit
cell division.
Ex: TGFb
inhibits phosphorylation of Rb