Controls the Cell Cycle Cell Signaling Controls the Cell Cycle

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

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.

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

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.

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

Signal Molecule Leads to Phosphorylation Cascade Amplification of cellular response

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

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

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.

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

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

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 (1920 - 1951)

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

Tumor Suppressor Genes Inhibit cell cycle May become defective from mutation

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

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

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

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

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)

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

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