1. Finish Cancer Lecture Tissues and Cell-Cell Interactions

2. Cancer Cells Are Created when Certain Genes are Mutated Mutations can be Inherited, Introduced by Viruses, or Result of DNA Damage 1. Oncogenes - Gene whose presence can trigger inappropriate cell proliferation. Example: ras, bcl-2 (Normal version of gene: Proto-oncogene) 2. Tumor Suppressors- Gene whose absence or inactivation can lead to cancer Usually Function to Block Cell Cycle Progression Example: p53, Rb DNA Repair Genes- Increase Rate of Mutation, provide opportunity for mutation in growth controlling genes, increase rate of tumor progression

3. Can Also Occur By: Overexpression of Proto-oncogene Translocations that create hybrid proteins Cancer Cells Are Created when Certain Genes are Mutated

4. Oncogenes are Found in Mitogen and Growth Factor Signal Transduction Pathways Mutation of Proto-oncogene- Constitutively Active Downstream Signal Transduction Pathway

5. Inactivation of Tumor Suppressor Rb Common Target for Viruses that Cause Tumors (along with p53)

6. Cancer Cells Exhibit Unlimited Proliferative Ability Cancer cells avoid Senescence by inactivating tumor suppressor genes, p53 and Rb. Cancer Cells will continue to divide for a period of time Crisis Point – Large number of Cancer Cells Die- Result of catastrophic rearrangements- due to lack of telomerase Rare Occasion A Cell Survives- It is Immortalized. At some point- de-repressed telomerase expression ~ 90% of cancer cells express significant levels of telomerase

7. Structural and Functional Framework of Animal Tissues: Formation and Maintenance 4 Main Types of Tissue- Nervous, Muscle, Epithelial and Connective Tissues Are Composed of: 1) Organized Groups of Cells with Similar Function 2) Extracellular Matrix (ECM)- Network of Proteins and Sugars that Lies in the Intercellular Spaces To Create and Maintain Tissues Cells Need to Adhere to One Another or to the ECM 1) Structure of the ECM 2) Cell-Cell and Cell-ECM Junctions Specialized Protein Complexes that Provide Specific Means of Joining Cells in Long Term Association 2) Cell-Cell and Cell-ECM Adhesion Molecules Transient Interactions involving Transmembrane Proteins Do Not form Stable Cell Junctions Proteins of ECM and Cell Junctions Control 3-D Organization of Cells in Tissues and Growth, Movement, Shape and Differentiation

8. ECM of Loose Connective Tissue

9. Supports Sheets of Epithelial Cells Surrounds Muscle, Adipose, and Peripheral Nerve Cells The Basal Lamina is A Specialized Form of Extracellular Matrix

10. The ECM of Animal Cells Composed of : 1) Structural Proteins- Give Strength and Flexibility Examples: Collagen and Elastin 2) Proteoglycans- Protein Polysaccharide Complexes Provide the Gel-Like Matrix in which Structural Proteins are Embedded 3) Adhesive Glycoproteins- Attach Cells to the Matrix and Matrix Proteins to Each Other Example: Fibronectins and Laminins Differences in Types of ECM Reflect Differences in : 1) The Types of Structural Proteins and Kinds of Proteoglycans Present 2) The Ratio of Structural Protein to Proteoglycans Present

11. Structural Proteins of the ECM 1)Collagens- Major Proteins of the ECM – Long, Stiff, Triple Stranded Collagen Super Helix –High Tensile Strength, Provide Mechanical Strength – Nearly all Animal Cells Synthesize and Secrete at least One Form of Collagen (27 Families of Collagen Exist) 2) Elastic Fibers –Impart Elasticity and Flexibility –Fibers Formed from Elastin and a Glycoprotein that forms a Sheath around Elastin

12. Assembly and Structure of Collagen Forms: Fibrillar, Fibril Associated, or Network Forming Once Assembled- Often Larger than Cells that Secreted Them! Three Strands Self Assemble In ER Fibrils and Fibers Only Assemble After Secretion

13. Elastic Fibers Impart Elasticity and Flexibility to the ECM -Strength Arises from Covalent Crosslinks -Abundant in: Blood vessels, skin, lungs -Only Assemble into Fibers After Secretion Blood Vessel Elastic Fibers

14. Collagen and Elastic Fibers Are Embedded in a Matrix of Proteoglycans Proteoglycans Protein Core with Glycosaminoglycans (GAGs)- Unbranched polysaccharide chains- Covalently Attached Function: Make Up the Hydrated Gel Like Network Resist Compressive Forces GAG Bristles Act as Filters- Limit Diffusion Can Bind Growth Factors, Structural Proteins, and Cell Surface Receptors Some are Transmembrane Proteins

15. Glycosaminoglycans (GAGs) Are Long Unbranched Polysaccharides of Repeating Disaccharides Example: Hyaluronan

16. Proteoglycans and GAGs Can Form Large Aggregates Aggregates from Cartilage

17. Third Component of ECM: Adhesive Glycoproteins Attach Cells to ECM and ECM components to One Another -Bind Collagen and Proteoglycans- Organize Matrix -Binding Site for Cell Surface Receptors called Integrins Fibronectins- Prototype for Adhesive Glycoproteins –Most Common Adhesive Glycoprotein –Approximately 50% Carbohydrate –Bind Cells to the Matrix and Guides Cellular Movement Laminins- –Distinct Adhesive Component of Specialized Basal Lamina –Function as a Structural Support and as a Permeability Barrier

18. Fibronectin binds Cell Surface Receptors Called Integrins Linking Cell Surface to ECM Fibronectin Focal Adhesions Involved in Cell Migration

19. Cells and their ECM Role of ECM in Cell Anchorage and Cell Spreading Cells Organize their ECM Cells must routinely degrade and replace their ECM – secrete Extracellular Matrix Proteases

20. Cell-Cell Adhesion and Cell-Matrix Adhesion

21. The Cadherin Superfamily Responsible for Ca 2+ Dependent Cell-Cell Adhesion in Vertebrates Main Adhesion Molecule Holding Cells Together in Early Embryonic Development Primarily Responsible for Stable Junctions involving Cytoskeleton Typically A Single Pass Transmembrane Glycoproteins

22. Cadherins Bind Primarily Through a Homophilic Mechanism

23. Cell-Cell and Cell-ECM Junctions Junctions: Specialized protein complexes that allow neighboring cells to adhere and communicate with one another Provide Specific Means of Joining Cells in Long Term Association to Form Tissues and Organs Three Functional Types of Junctions –Anchoring Junctions –Occluding Junctions –Communicating Junctions

24. Types of Cell Junctions Junctional Complex

25. Anchoring Junctions Link Cells Together into Tissues Enable Cells to Function as a Unit -Involve Anchoring Cytoskeleton of One Cell to the Cytoskeleton of Neighboring Cell or to ECM -Important for Tissues Subjected to Mechanical Stress -Three Types of Anchoring Junctions: -Adherens Junctions -Desmosomes -Hemidesmosomes

26. Anchoring Junctions: Adherens Junctions Link Actin Cytoskeleton of Adjacent Cells Function: To Hold Neighboring Cells Together Epithelial and Non-Epithelial Tissues 1) Involve Transmembrane Proteins called Cadherins 2) Provide Enough Strength for Tissue to Resist Stress/Change Shape

27. Anchoring Junctions: Desmosomes Indirectly Connect Intermediate Filaments of Adjacent Cells Key Function: Resisting Physical Stresses (Particularly to Epithelial Sheets) Epithelial and Nonepithelial Tissue Involve Non-Traditional Cadherin Proteins Anchor Proteins and Intermediate Filaments

28. Involve Integrins Which bind to Laminin of Basal Lamina Key Function: Provide Structural Stability to Epithelial Sheets Anchoring Junctions: Hemidesmosomes Attach Epithelial Cells to the Basal Lamina

29. Occluding Junctions: Tight Junctions Form Selectively Permeable Barriers between Epithelial and Endothelial Cells Functions: 1) Regulate Paracellular Transport (Transport in space between cells) 2) Prevent Diffusion of Membrane Proteins- Preserve Cell Polarity Involves Transmembrane Proteins from Adjacent Cells -Claudins, Occludins, and Junctional Adhesion Molecules (JAM) -Structural proteins

30. Experimental Evidence Demonstrating Tight Junctions Create a Selectively Permeable Barrier -The Seal is Not Absolute! -Variations in Selectivity of Barrier Exist

31. Communication Junctions: Gap Junctions Found in Most Animal Cells Function: Allow Electrical and Chemical Communication Between Cells Open Channel- Provides Point of Cytoplasmic Contact Between Two Adjacent Cells Formed by Connexons Like Ion Channels- Regulated Opening/Closing No Macromolecules - Just Inorganic Ions, Small Molecules

32. Communication Junctions: Gap Junctions

33. Transient Cell-Cell Adhesion: Role of Selectins and Integrins In Bloodstream Selectins: Transmembrane Proteins that binds Cell Surface Carbohydrates E, P and L Type Selectins Required for movement of WBC Out of Blood Vessel and Into Inflammed Tissue WBC only bind Epithelial Cells expressing both E and P selectins

34. Office Hours This Week Tuesday B430 Nelson 5:30- 7:30 pm