Transcript 1) Structural Proteins

Finish Cancer Lecture
Tissues and
Cell-Cell Interactions
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
Cancer Cells Are Created when
Certain Genes are Mutated
Can Also Occur By
Overexpression
of Proto-oncogene
Translocations
that create
hybrid proteins
Oncogenes are Found in Mitogen and
Growth Factor Signal Transduction Pathways
Mutation of Proto-oncogeneConstitutively Active Downstream
Signal Transduction Pathway
Inactivation of Tumor Suppressor Rb
Common Target for Viruses that
Cause Tumors
(along with p53)
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
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
ECM of Loose Connective Tissue
The Basal Lamina is A Specialized Form of
Extracellular Matrix
• Supports Sheets of Epithelial Cells
• Surrounds Muscle, Adipose, and Peripheral Nerve Cells
The ECM of Animal Cells
Composed of :
1) Structural ProteinsGive 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 GlycoproteinsAttach 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
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
Assembly and Structure of Collagen
Fibrils and Fibers
Only Assemble
After Secretion
Once Assembled- Often
Larger than Cells that
Secreted Them!
Three Strands
Self Assemble
In ER
Forms: Fibrillar, Fibril Associated, or Network Forming
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
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
Glycosaminoglycans (GAGs) Are Long Unbranched
Polysaccharides of Repeating Disaccharides
Example: Hyaluronan
Proteoglycans and GAGs Can
Form Large Aggregates
Aggregates from Cartilage
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
Fibronectin binds Cell Surface Receptors Called
Integrins Linking Cell Surface to ECM
Fibronectin
Focal Adhesions
Involved in
Cell Migration
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
Cell-Cell Adhesion and Cell-Matrix Adhesion
The Cadherin Superfamily
• Responsible for Ca2+ 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
Cadherins Bind Primarily Through
a Homophilic Mechanism
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
Types of Cell Junctions
Junctional
Complex
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
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
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
Anchoring Junctions:
Hemidesmosomes Attach Epithelial
Cells to the Basal Lamina
Key Function:
Provide Structural Stability to
Epithelial Sheets
Involve
Integrins
Which
bind to
Laminin of
Basal Lamina
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
Experimental Evidence Demonstrating Tight
Junctions Create a Selectively Permeable Barrier
-The Seal is Not Absolute!
-Variations in Selectivity of Barrier Exist
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
No Macromolecules Just Inorganic Ions, Small Molecules
Formed by Connexons
Like Ion Channels- Regulated Opening/Closing
Communication Junctions:
Gap Junctions
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
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