BBS2042 All
Cases
,Table of Contents
Case 1: The cellular intra- and internet .......................................................................................... 5
1. Explain the different kinds of cell junctions .................................................................................... 5
2. What are the different types of signaling? (crines) + feedback loops, hormones, distances to
signal.................................................................................................................................................. 19
3. What different receptors are involved? (Only classification) ....................................................... 24
4. Examples of signaling pathways .................................................................................................... 26
Case 2: Listen very carefully, I will tell you this (more than) once ................................................. 28
1. Different classes of signal molecules - First the general types (hormone, neurotransmitter etc.) -
Then properties (like hydrophilic, lipophilic)..................................................................................... 28
2. Production of signal molecules in the cell + (partly) secretion and transport .............................. 32
3. How is the signal received by the target cell and which function does the signal perform? ....... 39
4. Gasotransmitters, Louis Ignarro NO + other molecules ........................................................... 43
5. Neurotransmitters, types and mechanisms .................................................................................. 47
6. Secretion from the cell, extracellular vesicles ............................................................................... 53
7. Protein secretion pathways ........................................................................................................... 59
Case 3: Signaling to degrade mRNA ............................................................................................. 70
1. What is RNAi? - Types: sh, micro, lnc, si - Evolution / history - PKR reaction ............................... 70
2. Production of RNAi ........................................................................................................................ 74
3. Secretion of RNAi + traveling......................................................................................................... 78
4. Function of RNAi - Received by target cell .................................................................................... 81
Case 4: From outside to inside without entering .......................................................................... 86
1. Structure + function different types of receptors that induce signal transduction (General
principles cell signaling included) ...................................................................................................... 86
2. GCPR + G protein pathway + the scheme in the case ................................................................... 89
3. Enzyme-coupled receptor pathway ............................................................................................ 103
4. Ras pathway - Role in tumors / oncogenes ................................................................................. 120
5. Examples of where these pathways come in play....................................................................... 122
Case 5: What happens when signals go nuclear? ........................................................................124
1. Structure of nuclear receptors different types....................................................................... 124
2. Function of nuclear receptors different types........................................................................ 126
, 2A. Consensus sequences................................................................................................................ 128
3. PPARs + PPREs pathway + vitamin A - What is the link of PPARs to lipids? ............................ 129
Case 6: How to deal with foreign chemical exposures? ...............................................................132
1. Structure, function of AhR pathway ............................................................................................ 132
2. How does TCDD work? - Short-term and long-term effects of TCDD - Normal levels - Binding to
AhR .................................................................................................................................................. 139
3. Detoxification of xenobiotics example of dioxins - How are we exposed to xenobiotics? .... 142
4. The effect of diet on AhR............................................................................................................. 144
Case 7: Signaling now for in the future .......................................................................................148
1. What is BPA? - Structure + how are we exposed? ...................................................................... 148
2. Function and (long-term) effects of BPA - Endocrine disruptor - Link of BPA with diabetes and
cancer .............................................................................................................................................. 150
3. Detoxification of BPA................................................................................................................... 157
4. Consequences of prenatal exposure to BPA ............................................................................... 158
Case 8: Oxidative stress, the good, the bad and the ugly .............................................................160
1. Common forms of ROS and formation (Where do they come from?) .................................... 160
2. How does ROS redox signaling affect cell functions / homeostasis (balance and disbalance) -
Damaging proteins, DNA damage ................................................................................................... 162
3. Cancer and Alzheimer in relation to ROS (see also LG2 for link with cancer) ............................. 167
4. Types and production of antioxidants - Keap1-Nrf2 - Cullin 3 .................................................... 173
Case 9: Incoming and outgoing signals .......................................................................................181
1. What is mTOR (C1 and C2)? – Structural differences .................................................................. 181
2. mTOR pathway activation - Extracellular - Intracellular.............................................................. 183
3. mTOR pathway inhibition - Endogenous - Exogenous ................................................................ 192
4. Healthy vs. unhealthy effects (diseasescancer, diabetes, aging) ............................................ 193
Case 10: The CRISP(Y) case .........................................................................................................200
1. What are CRISPR and Cas9? ........................................................................................................ 200
2. The CRISPR pathway in bacteria .................................................................................................. 201
3. How is it applied to humans? ...................................................................................................... 210
4. BRCA pathway and breast cancer ............................................................................................... 213
5. Application of CRISPR/Cas9 in breast cancer .............................................................................. 216
, Case 11: How to use the toolbox? ............................................................................................217
1. Pathology of cardiac hypertrophy and the role of cell signaling ................................................. 217
2. Pathology of acute lymphocytic leukemia and the role of cell signaling .................................... 221
Case 13: From mutations to cancer ............................................................................................224
1. Steps in cancer formation, hallmarks of cancer .......................................................................... 224
2. How are tumor suppressor genes and oncogenes involved in cancer? ...................................... 233
3. How can carcinogens cause mutations? ..................................................................................... 240
4. Colon cancer & heritability .......................................................................................................... 243
,Case 1: The cellular intra- and internet
Problem: Cell-cell communication
Learning goals
1. Explain the different kinds of cell junctions
2. What are the different types of signaling? (crines)
- + distances to signal
3. What different receptors are involved? (Only classification)
1. Explain the different kinds of cell junctions
Sources:
- The Cell, Chapter 19
- Silverthorn, Chapter 3
Overview
There are two broad categories of tissues in all animals: connective tissues and epithelial tissues.
• Connective tissues consist of an extracellular matrix (ECM) produced by cells that are
distributed sparsely in the matrix. The matrix bears most of the mechanical stress to which
the tissue is subjected. Cell-matrix junctions link the cytoskeleton to the matrixcells can
move through the matrix and monitor changes in its mechanical properties.
• Epithelial tissues consist of cells that are tightly bound together into sheets called epithelia.
These tissues have a thin ECM called the basal lamina / basement membrane, which
underlies the sheet.
o Cell-cell junctions attach cells in the epithelium to each other. At these junctions,
cytoskeletal filaments are anchored that transmit stresses through the cells, from
one adhesion to another.
o Cell-matrix junctions link the cytoskeleton to the basal lamina.
o In a simple columnar epithelium, a single layer of tall cells is located on a basal
lamina.
o The apex (uppermost surface of the cells) is exposed to the extracellular medium.
5
,o The cells connect to each other on their lateral surfaces.
o Two types of anchoring junctions link the cytoskeletons of adjacent cells:
▪ Adherens junctions connect actin filament bundles
▪ Desmosomes connected intermediate filaments
o The cytoskeleton is linked to the basal lamina by two additional types of anchoring
junctions:
▪ Actin-linked cell-matrix junctions anchor actin filaments to the matrix
▪ Hemidesmosomes anchor intermediate filaments to the matrix
o There are also tight junctions and gap junctions:
6
, ▪ Tight junctions hold the cells closely together near the apex. This prevents
leakage of molecules across the epithelium.
▪ Gap junctions are located near the basal end of the cells. They are channel-
forming junctions that link the cytoplasm of adjacent cells.
o The four anchoring junction types depend on transmembrane adhesion proteins
that span the plasma membrane. One end links to the cytoskeleton inside the cell
and the other end links to extracellular structures.
o There are two super-families of these proteins:
▪ Cadherins mediate cell to cell attachment
▪ Integrins mediate cell to matrix attachment
o There is specialization within each family: some cadherins link to actin and form
adherens junctions, while others link to intermediate filaments and form
desmosomes; likewise, some integrins link to actin and form actin-linked cell–matrix
junctions, while others link to intermediate filaments and form hemidesmosomes.
Cell-cell junctions
The two types of cell-cell anchoring junctions link the cytoskeleton of one cell with that of its
neighbor. Their main function is to resist the external forces that pull cells apart.
7
Cases
,Table of Contents
Case 1: The cellular intra- and internet .......................................................................................... 5
1. Explain the different kinds of cell junctions .................................................................................... 5
2. What are the different types of signaling? (crines) + feedback loops, hormones, distances to
signal.................................................................................................................................................. 19
3. What different receptors are involved? (Only classification) ....................................................... 24
4. Examples of signaling pathways .................................................................................................... 26
Case 2: Listen very carefully, I will tell you this (more than) once ................................................. 28
1. Different classes of signal molecules - First the general types (hormone, neurotransmitter etc.) -
Then properties (like hydrophilic, lipophilic)..................................................................................... 28
2. Production of signal molecules in the cell + (partly) secretion and transport .............................. 32
3. How is the signal received by the target cell and which function does the signal perform? ....... 39
4. Gasotransmitters, Louis Ignarro NO + other molecules ........................................................... 43
5. Neurotransmitters, types and mechanisms .................................................................................. 47
6. Secretion from the cell, extracellular vesicles ............................................................................... 53
7. Protein secretion pathways ........................................................................................................... 59
Case 3: Signaling to degrade mRNA ............................................................................................. 70
1. What is RNAi? - Types: sh, micro, lnc, si - Evolution / history - PKR reaction ............................... 70
2. Production of RNAi ........................................................................................................................ 74
3. Secretion of RNAi + traveling......................................................................................................... 78
4. Function of RNAi - Received by target cell .................................................................................... 81
Case 4: From outside to inside without entering .......................................................................... 86
1. Structure + function different types of receptors that induce signal transduction (General
principles cell signaling included) ...................................................................................................... 86
2. GCPR + G protein pathway + the scheme in the case ................................................................... 89
3. Enzyme-coupled receptor pathway ............................................................................................ 103
4. Ras pathway - Role in tumors / oncogenes ................................................................................. 120
5. Examples of where these pathways come in play....................................................................... 122
Case 5: What happens when signals go nuclear? ........................................................................124
1. Structure of nuclear receptors different types....................................................................... 124
2. Function of nuclear receptors different types........................................................................ 126
, 2A. Consensus sequences................................................................................................................ 128
3. PPARs + PPREs pathway + vitamin A - What is the link of PPARs to lipids? ............................ 129
Case 6: How to deal with foreign chemical exposures? ...............................................................132
1. Structure, function of AhR pathway ............................................................................................ 132
2. How does TCDD work? - Short-term and long-term effects of TCDD - Normal levels - Binding to
AhR .................................................................................................................................................. 139
3. Detoxification of xenobiotics example of dioxins - How are we exposed to xenobiotics? .... 142
4. The effect of diet on AhR............................................................................................................. 144
Case 7: Signaling now for in the future .......................................................................................148
1. What is BPA? - Structure + how are we exposed? ...................................................................... 148
2. Function and (long-term) effects of BPA - Endocrine disruptor - Link of BPA with diabetes and
cancer .............................................................................................................................................. 150
3. Detoxification of BPA................................................................................................................... 157
4. Consequences of prenatal exposure to BPA ............................................................................... 158
Case 8: Oxidative stress, the good, the bad and the ugly .............................................................160
1. Common forms of ROS and formation (Where do they come from?) .................................... 160
2. How does ROS redox signaling affect cell functions / homeostasis (balance and disbalance) -
Damaging proteins, DNA damage ................................................................................................... 162
3. Cancer and Alzheimer in relation to ROS (see also LG2 for link with cancer) ............................. 167
4. Types and production of antioxidants - Keap1-Nrf2 - Cullin 3 .................................................... 173
Case 9: Incoming and outgoing signals .......................................................................................181
1. What is mTOR (C1 and C2)? – Structural differences .................................................................. 181
2. mTOR pathway activation - Extracellular - Intracellular.............................................................. 183
3. mTOR pathway inhibition - Endogenous - Exogenous ................................................................ 192
4. Healthy vs. unhealthy effects (diseasescancer, diabetes, aging) ............................................ 193
Case 10: The CRISP(Y) case .........................................................................................................200
1. What are CRISPR and Cas9? ........................................................................................................ 200
2. The CRISPR pathway in bacteria .................................................................................................. 201
3. How is it applied to humans? ...................................................................................................... 210
4. BRCA pathway and breast cancer ............................................................................................... 213
5. Application of CRISPR/Cas9 in breast cancer .............................................................................. 216
, Case 11: How to use the toolbox? ............................................................................................217
1. Pathology of cardiac hypertrophy and the role of cell signaling ................................................. 217
2. Pathology of acute lymphocytic leukemia and the role of cell signaling .................................... 221
Case 13: From mutations to cancer ............................................................................................224
1. Steps in cancer formation, hallmarks of cancer .......................................................................... 224
2. How are tumor suppressor genes and oncogenes involved in cancer? ...................................... 233
3. How can carcinogens cause mutations? ..................................................................................... 240
4. Colon cancer & heritability .......................................................................................................... 243
,Case 1: The cellular intra- and internet
Problem: Cell-cell communication
Learning goals
1. Explain the different kinds of cell junctions
2. What are the different types of signaling? (crines)
- + distances to signal
3. What different receptors are involved? (Only classification)
1. Explain the different kinds of cell junctions
Sources:
- The Cell, Chapter 19
- Silverthorn, Chapter 3
Overview
There are two broad categories of tissues in all animals: connective tissues and epithelial tissues.
• Connective tissues consist of an extracellular matrix (ECM) produced by cells that are
distributed sparsely in the matrix. The matrix bears most of the mechanical stress to which
the tissue is subjected. Cell-matrix junctions link the cytoskeleton to the matrixcells can
move through the matrix and monitor changes in its mechanical properties.
• Epithelial tissues consist of cells that are tightly bound together into sheets called epithelia.
These tissues have a thin ECM called the basal lamina / basement membrane, which
underlies the sheet.
o Cell-cell junctions attach cells in the epithelium to each other. At these junctions,
cytoskeletal filaments are anchored that transmit stresses through the cells, from
one adhesion to another.
o Cell-matrix junctions link the cytoskeleton to the basal lamina.
o In a simple columnar epithelium, a single layer of tall cells is located on a basal
lamina.
o The apex (uppermost surface of the cells) is exposed to the extracellular medium.
5
,o The cells connect to each other on their lateral surfaces.
o Two types of anchoring junctions link the cytoskeletons of adjacent cells:
▪ Adherens junctions connect actin filament bundles
▪ Desmosomes connected intermediate filaments
o The cytoskeleton is linked to the basal lamina by two additional types of anchoring
junctions:
▪ Actin-linked cell-matrix junctions anchor actin filaments to the matrix
▪ Hemidesmosomes anchor intermediate filaments to the matrix
o There are also tight junctions and gap junctions:
6
, ▪ Tight junctions hold the cells closely together near the apex. This prevents
leakage of molecules across the epithelium.
▪ Gap junctions are located near the basal end of the cells. They are channel-
forming junctions that link the cytoplasm of adjacent cells.
o The four anchoring junction types depend on transmembrane adhesion proteins
that span the plasma membrane. One end links to the cytoskeleton inside the cell
and the other end links to extracellular structures.
o There are two super-families of these proteins:
▪ Cadherins mediate cell to cell attachment
▪ Integrins mediate cell to matrix attachment
o There is specialization within each family: some cadherins link to actin and form
adherens junctions, while others link to intermediate filaments and form
desmosomes; likewise, some integrins link to actin and form actin-linked cell–matrix
junctions, while others link to intermediate filaments and form hemidesmosomes.
Cell-cell junctions
The two types of cell-cell anchoring junctions link the cytoskeleton of one cell with that of its
neighbor. Their main function is to resist the external forces that pull cells apart.
7
