1. Controls the Cell Cycle
Cell Signaling
Controls the Cell Cycle

2. Cell Signaling Ligand- a signal molecule binds to cell membrane.
Signal transduction - Converts signal from outside cell to inside

3. The Membrane Receptors
Gated ion channels - remember neurons. Depolarization resulted in opening of these channels.
G-Proteins - Ligand causes conformational change in receptor.
Triggers a signal transduction pathway
Receptor Tyrosine Kinases - Ligand causes dimerization of 2 receptors.
Can trigger several different pathways at once.

4. G-Proteins Like an on/off switch for the enzyme
Activated receptor activates G-Protein
G-Protein hydrolyzes its bound GTP, deactivates itself
G-Protein activates enzyme

5. Receptor Tyrosine Kinases
Each RTK phosphorylates tyrosines on the other polypeptide. Receptor is now fully activated.
Part of receptor protein in cytoplasm is an enzyme, tyrosine kinase, that catalyzes the transfer of phosphate group from ATP to tyrosine.
One RTK can activate up to 10 different cellular pathways.

6. Signal Transduction Pathways
Series of molecular interactions leading to a response in a cell.
In each step, signal is transduced to a different form.
Often a conformational change in a protein
Can amplify cellular response to a single ligand

7. Signal Molecule Leads to Phosphorylation Cascade
Amplification of cellular response

8. Cellular Responses
Often, signal transduction pathway results in activation of a transcription factor
Will “turn on” a particular gene

9. The Role of Cell Signaling in the Cell Cycle
Protein kinases are extremely important in regulation of cell processes.
2% of our genes code for kinases.
Recall that the cell cycle is regulated by proteins
Cyclins and CDKs

10. Signaling and the Cell Cycle
Growth factors = ligands
Platelet derived GF - triggers division of fibroblasts
PDGF receptor is a receptor tyrosine kinase.
Binding triggers signal transduction pathway that allows cell to pass G1 checkpoint.

11. Growth factor signals growth factor cell division cell surface
nuclear pore
E2F is a group of genes that codifies a family of transcription factors (TF) in higher eukaryotes.
Among E2F transcriptional targets are cyclins, cdks, checkpoints regulators, DNA repair and replication proteins.
The Rb tumour suppressor protein (pRb) binds to the E2F-1 transcription factor preventing it from interacting with the cell's transcription machinery. In the absence of pRb, E2F-1 mediates the trans-activation of E2F-1 target genes that facilitate the G1/S transition and S-phase.
nuclear membrane P P
cell division
cell surface
receptor
Cdk
E2F
protein kinase
cascade P
chromosome P Rb P
E2F Rb
cytoplasm
nucleus

12. Cancerous Cells Have Lost Control
In some cases, abnormal tyrosine kinases can dimerize in the absence of a signal and trigger cell division without GF
Some cancer cell make their own GF

13. Cancerous Cells Have Lost Control
Stop dividing at random points in cell cycle rather than at checkpoints
Immortal -
Normal cells divide 20-50x
Ex: HeLa cells (1951)
Henrietta Lacks ( )

14. Proto-oncogenes Initiate cell division at correct times
When mutated, may become oncogenes - overactive proto- oncogenes initiate cell cycle too frequently

15. Tumor Suppressor Genes
Inhibit cell cycle
May become defective from mutation

16. Cancer develops only after a cell experiences ~6 key mutations (“hits”)
Unlimited growth
turn on growth promoter genes
Ignore checkpoints
turn off tumor suppressor genes (p53)
Escape apoptosis
turn off suicide genes
Immortality = unlimited divisions
turn on chromosome maintenance genes
Promotes blood vessel growth turn on blood vessel growth genes
Overcome anchor & density dependence
turn off touch-sensor gene
Text

17. What causes these “hits”?
UV radiation
chemical exposure
radiation exposure
cigarette smoke
pollution
genetics

18. Cancer as a Disease
A single cell in a tissue undergoes a transformation from normal --> cancerous
Usually detected by immune system (cytotoxic T-cells)
If cell proliferates, forms a tumor
Benign - excessive division, but cells remain at original location

19. Cancer as a Disease
Malignant tumors - cells invade neighboring tissues due to several abnormal phenotypes
# of chromosomes (cause or effect?)
Metabolism - plays no useful role
Poor attachment to neighbors - abnormal cell surface. Cells may detach into blood or lymph vessels. This is metastasis
May secrete signals causing blood vessels to grow closer

20. Cancer Treatment Localized tumors - Radiation
High-energy radiation damages DNA in cancer cells. They cannot repair as normal cells do
Metastasized tumors - Chemotherapy
Drugs toxic to actively dividing cells
Symptoms caused by damage to healthy, fast dividing cells. (nausea, hair loss, decreased immune response)

21. New “miracle drugs”
Drugs targeting proteins (enzymes) found only in cancer cells
Gleevec
treatment for adult leukemia (CML) & stomach cancer (GIST)
1st successful drug targeting only cancer cells
Proof of Principle: you can treat cancer by targeting cancer-specific proteins.
GIST = gastrointestinal stromal tumors, which affect as many as 5,000 people in the United States
CML = chronic myelogenous leukemia, adult leukemia, which affect as many as 8,000 people in the United States
Fastest FDA approval — 2.5 months
without Gleevec
with Gleevec

22. Any Questions??