CB25 lec7 Signal Transduction I

Week's Overview

  • Next Week's Plan (3/3-3/7)

  • Monday: Lecture & Lab 4 (MTT assay)

  • Tuesday: Lecture & Cell Preparation

  • Wednesday: Chemical Treatment (~15 minutes)

  • Thursday: MTT Reaction (10 min - 1 hr wait - 5 min)

  • Friday: Spectrophotometry & Discussion

Course Information

  • Course: BIOL365 Cancer Biology

  • Lecture: 7

  • Topic: Signal Transduction (Chapter 6)

Signal Transduction Basics

  • Key Components:

    • Extracellular Signal Molecule: initiates signaling

    • Cell-Surface Receptor Protein: binds the signal molecule

    • Intracellular Signaling Pathway: transmits signal into the cell

    • Nucleus: target for signaling, affecting DNA

    • FAST Response: occurs in sec to mins, alters protein function

    • SLOW Response: occurs in mins to hrs, alters RNA and protein synthesis

    • Effects: Altered cytoplasmic machinery and cell behavior

Growth Factors and Gene Expression

  • Immediate Early Genes (IEG): Induction of ~100 genes within 30 minutes

    • Conditions: Cells must be starved for several days to enter G0 phase

    • Activation: Serum addition stimulates gene expression and proliferation

    • Signaling Proteins:

      • Serine/Threonine kinases: play a role in transduction

      • Transcription Factors: necessary for IEG transcription

    • Cycloheximide Effect: Inhibiting translation does not prevent IEG transcription

Cancer and Signal Processing

  • Aberrant Signaling: Main cause of cancer

    • Growth Factor Receptors (GFR): Release diverse biochemical signals

    • Immediate vs. Delayed Early Genes:

      • Some IEGs function as transcription factors (e.g., Myc) and are proto-oncogenes

Intracellular Signal Activation

  • Key Players:

    • G-Proteins: critical for signal transduction

    • GEF (Guanosine Exchange Factor): activates G-proteins

    • GAP (GTPase Activating Protein): regulates G-protein activity

    • Kinases: Serine/threonine and tyrosine kinases involved in signaling pathways

Mechanisms and Interactions in Cancer

  • Ras Pathway: Activated by GEF, important for signaling

    • Drosophila Example: Missing R7 cells (Sevenless gene) leads to developmental abnormalities

    • Signaling Pathway: RTK → Shc → Grb → Sos → Ras activation

Adaptor Proteins and Signal Complexity

  • SH Domains:

    • SH1: Kinase domain

    • SH2: Binds phosphorylated tyrosine residues

    • SH3: Binds proline-rich motifs in partner proteins

    • Diversity: Human genome encodes numerous SH2 domains for various adaptors

Ras Effectors and Cellular Behavior

  • Ras: Anchored to cell membrane; activation leads to downstream effects

    • Raf Kinase: Affects gene expression and cell cycle regulation

    • IEGs (Fos, Jun): Form AP-1 transcription factor complex influencing proliferation

    • Cancer Mutations: ~50% of melanoma cases involve B-Raf mutation

Phosphoinositide Signaling

  • Lipid Components:

    • Phosphatidylinositol: Key in cell membrane signaling

    • Key Enzymes: PLC (Phospholipase C) involved in generating secondary messengers

  • PI3K Pathway:

    • Akt/PKB: Key oncogene with diverse roles in cellular processes

    • PTEN: Tumor suppressor gene regulating PI3K/Akt activity

Pathway Deregulation in Cancer

  • PI3K Activation: Found hyperactive in many cancers

    • Common Mutations: PTEN function loss through mutations or epigenetic changes

    • Cancer Stats: 30-40% of human cancers show PTEN activity loss

Immediate Early Genes Overview

  • Gene Features:

    • Functionality: Components of transcription factors, cytoskeletal proteins, etc.

    • Examples: Fosb, JunB, Myc, involved in cellular growth and maintenance

    • Adaptation: IEGs can impact cancer pathways; highlighted research findings offer insights into their roles

Important Findings Related to PI3K

  • PI3K Structure: Understanding binding domains and their implications for signaling pathways

  • Interaction Complexity: The role of Ras and associated proteins in cellular growth and cancer progression