Chapter 1: The Cell as a Unit of Health and Disease Flashcards
1
Q
SNPs and the causative genetic factor are said to be in what?
A
Linkage disequilibrium
2
Q
Most of the genetic variations/polymorphisms associated with disease are found where in the genome?
A
Non-protein coding regions
3
Q
What are SNPs and they are almost always what?
A
- Single nucleotide polymorphisms
- Almost always biallelic (only two choices exist, such as A or T)
4
Q
What type of chromatin is lightly staining and lightly packed, is it active or inactive?
A
- Euchromatin
- Transcriptionally active
5
Q
What type of chromatin is dark staining and tightly packed, is it active or inactive?
A
- Heterochromatin
- Transcriptionally inactive
6
Q
Heritable changes in gene expression that are not caused by alteration in DNA sequence is the definition of?
A
Epigenetics
7
Q
Which AA’s of Histones can be methylated?
A
Lysines and Arginines
8
Q
Which Histone is the linker protein and its function?
A
- H1
- Stabilizes the overall chromatin architecture
9
Q
DNA methylation results in what?
A
Transcriptional silencing
10
Q
Which AA’s of histones are acetylated and by what enzyme?
What does this do?
A
- LYSINE residues
- Histone acetyl transferase (HAT)
- Open up the chromatin and increase transcription
11
Q
Histone phosphorylation results in what and what residue is modified?
A
- Serine residue
- Depending on residue may be opened up for transcription or made inactive
12
Q
Epigenetic alterations are reversible and what are two ways they have already been treated therapeutically?
A
- HDAC inhibitors
- DNA methylation inhibitors
13
Q
What is the primary function of miRNA and how are they related to gene expression?
A
- Modulate the translation of target mRNAs into their corresponding proteins
- Post-transcriptional silencing of gene expression that is highly conserved and present in all eukaryotes
14
Q
Describe the process of gene silencing starting with primary miRNA.
Through what mechanisms may gene silencing occur?
A
Pri-miRNA –> pre-miRNA –> cleaved by DICER –> dsmiRNA -> mature ss-miRNA which associates with RISC -> binds target mRNA
- Binding of miRNA + RISC complex to target mRNA, the mRNA is either degraded (perfect match) or repressed (imperfect match)
15
Q
All mRNA’s contain a ________ that determines the specificity of miRNA binding and gene silencing (what sequence)
A
All mRNA’s contain a 3’ seed sequence in their untranslated region (UTR) that determines the specificity of miRNA binding and gene silencing
16
Q
What are the short RNA sequences introduced into cells experimentally that act as substrates for DICER + interact with the RISC complex analagous to endogenous miRNAs?
Why are they useful in the lab?
A
- Small interfering RNAs (siRNAs)
- Useful to knockdown target genes in the lab and as a potential therapeutic strategy (i.e., knockdown oncogenes in neoplastic transformations)
17
Q
How do lncRNAs modulate gene expression; what is the best known example of an lncRNA?
A
- Bind chromatin and restrict RNA polymerase access = gene silencing
- XIST, which is transcribed from X chromosome and plays a role in physiologic X chromosome inactivation
18
Q
What are the 4 ways lncRNA’s can affect DNA?
A
1) Gene activation
2) Gene suppression
3) Promote chromatin methylation and acetylation
4) Assemble protein complexes
19
Q
In what cell types is the SER abundant in?
Used for what processes?
A
- Gonads and liver
- Steroid hormone and lipoprotein synthesis
- Modification of hydrophobic compounds (i.e., drugs) into water-soluble molecules for excretion!
20
Q
After denatured proteins are chewed up by proteosomes, some of the peptides are presented by what?
A
MHC class I
21
Q
Antigen presentation in the context of intracellular pathogens (i.e., virally infected cells) requires what 2 things?
A
- Proteosomal degradation
- Loading in to MHC class I
22
Q
Peroxisomes have a specialized role in; what do they produce?
A
- Specialized role in breakdown of fatty acids
- Produce hydrogen peroxide
23
Q
Which lipid of the plasma membrane is a marker for apoptosis and how does this work; what is the other important function of this lipid?
A
- Phosphatidylserine
- Normally found on inner face, however, when it flips to extracellular face it serves as “eat me” signal for phagocytes
- Serves as cofactor for platelets in the clotting of blood
24
Q
What lipid can be phosphorylated and serve as electrostatic scaffold for intracellular proteins?
Can also be what?
A
- Phosphatidylinositol
- Hydrolyzed by PLC to generate DAG and IP3
25
What is responsible for pumping polar compounds (chemotherapeutic drugs) OUT of cells and may render cancer cells resistant to treatment?
MDR protein
26
If a protein does not contain a signal sequence, where does translation occur?
Free ribosomes in the cytosol
27
What are the lipids found attached to the outer leaflet of the plasma membrane?
- Phosphatidylcholine
- Sphingomyelin/Glycolipids
28
What may serve as an anchor for proteins to the extracellular leaflet of the plasma membrane?
Glycosylphosphatidylinositol (GPI)
29
In caveolae-mediated endocytosis noncoated PM invaginations are associated with what?
They are implicated with the regulation of transmembrane signaling via the internalization of what?
- GPI-linked molecules, cAMP binding proteins, SRC-family kinases and the folate receptor
- Internalization of receptors and integrins
- Can also be used to bring in folate
30
How does a small, polar molecule like alcohol cross membranes?
What are other examples of molecules that use this method?
- Passive membrane diffusion
- O2 , CO2 (gases), and hydrophobic molecules (steroids)
- Polar molecules smaller than **75 Da** (**water, ethanol, urea**)
31
What protein is a transporter ATPase that pumps polar compounds (i.e., chemotherapeutic drugs) out of cells and may render cancer cells resistant to treatment?
Multidrug resistant (MDR) protein
32
What is the major uptake mechanism for LDL and transferrin and why are they taken up into the cell?
Defects in LDL uptake lead to?
- Receptor-mediated endocytosis
- LDL and transferrin then **release their cargo** (cholesterol and iron) in the lysosome
- Defect in receptor-mediated transport of LDL responsible for **familial hypercholesterolemia**
33
What is the movement of endocytosed vesicles between the apical and basolateral compartments of the cell called; what is an important example of this process?
- Transcytosis
- Allows for transfer of large amounts of intact proteins across epithelial barriers
- Ingested Ab's in maternal milk across intestinal epithelia
34
What cell-cell or cell-matrix interaction/process is involved in leukocyte extravasation?
- Tight junctions
- Transcytosis (called diapedesis)
35
Actin is formed from what and why is this protein significant?
- Globular protein G-actin
- Most abundant cytosolic protein in cells
36
What is the function of F-actin in muscle cells and non-muscle cells?
- Muscle cells, binds to actin, and moves it along, driven by ATP-hydrolysis
- Non-muscle cells, assembles into well-organized bundles/networks that control cells shape and movement
37
What is the function of Intermediate filaments and describe their properties?
- Tensile strength, allow cells to bear mechanical stress
- **Rope-like** and found mostly in the polymerized form and do not actively reorganize lik actin and microtubules do.
38
The major component of skin and hair, keratin, is composed of what?
Keratin = **intermediate filament**
39
There are multiple types of intermediate filaments depending on the cell type, list 6 of them.
1) Lamin A, B, and C (nuclear lamina of all cells)
2) Vimentin: mesenchymal cells (fibroblasts, endothelium)
3) Desmin (muscle cells, the scaffold on which actin and myosin contract)
4) Neurofilaments (axons of neurons, imparting strength and rigidity)
5) Glial fibrillary acidic protein (glial cells around neurons)
6) Cytokeratins (subdivided into acidic (type I) and neutral/basic (type II))
40
What are cytokeratins and how are they divided?
Can be used as?
- Type of intermediate filament, with at least 30 different varieties
- Subdivided into **acidic (type I)** and **basic/neutral (type II)**
- Different types in different cells, can be used as **cell markers**
41
Describe the structure of Microtubules
- Noncovalently polymerized dimers of α- and β-tubulin arranged in dynamic hollow tubes with defined polarity
- The ends are designated "+" or "-"
42
Where is the "-" end of microtubules found and what about the "+" end?
- The "-" end is typically **embedded** in a ***microtubule organizing center*** **(MTOC or centrosome)** near the nucleus where it is associated with paired centrioles
- The "+" end **elongates** or **recedes** in response to various stimuli by the addition or subtraction of tubulin dimers
43
Within cells microtubules can also serve as connecting cables for molecular motor proteins that use ATP to move vesicles, organelles, or other molecules along microtubules, what are these motor proteins and in which direction does each move?
- **Kinesins** are for **anterograde** transport
- **Dyneins** for **retrograde** transport
44
What is the function of microtubules/molecular motor proteins during mitosis and what other functions have they adapted to perform?
- Sister chromatid separation during mitosis
- Adapted to form **motile cilia** (i.e., bronchial epithelium) or **flagella** (sperm)
45
Occluding junctions (tight junctions) have what function and what transmembrane proteins make up these complexes?
- Seal cells together to create a continous barrier, restricting paracellular movement of ions and other molecules
- **Occludin, claudin, zonulin,** and **catenin**
\*These junctions are **dynamic** structures that can dissociate and reform as required to facilitate epithelial proliferation or inflammatory cells migration (EXAM Q)
46
Cadherins are associated with what cell-cell interaction?
Integrins?
- Cadherins associated w/ Desmosomes
- Integrins associated w/ Hemidesmosomes
47
What are the cadherins of spot desmosomes vs. belt desmosomes; what is each linked to?
- **Spot** desmosomes, the cadherins are **desmogleins** and **desmocollins** (linked to IC intermediate filaments)
- **Belt** desmosomes, the cadherins are called **E-cadherins** (linked to IC actin microfilaments)
48
What are the large macromolecular complexes that can be localized at hemidesmosomes and include proteins that can generate intracellular signals when cells are subjected to increased shear stress?
Focal Adhesion Complexes
49
What organelle is responsible for sequestering intracellular calcium?
What is it called in muscle cells?
- SER
- Sarcoplasmic reticulum (in myocytes)
50
What is the relationship of the permeability of gap junctions to intracellular pH and Ca2+?
- Permeability reduced by lowered pH or increased Ca2+
51
The ER lumen is topologically equivalent to what?
Extracellular enviornment
52
Repeated exposure to compounds that are metabolized by the SER (i.e., phenobarbitol catabolism by the CYP450 system) can lead to what?
Reactive SER hyperplasia
53
The CFTR protein mutation causes the absence of which single AA and leads to what?
- Phe508
- Misfolding, ER retention, and degradation of the CFTR protein
- Excess accumulation of misfolded proteins, exceeding capacity of the ER to edit and degrade them leads to ER **stress response** (unfolded protein response) that triggers **cell death** through **apoptosis**
54
What is the function of the cis Golgi network and the trans Golgi network?
- Cis golgi network recycles protein back to the ER
- Trans golgi network sorts proteins and lipids and dispatches them to other organelles (including the PM) or to secretory vesicles for extracellular release
55
Where is the Golgi complex especially prominent?
- Cells **specialized** for **SECRETION**
- Goblet cells of the intestine
- Bronchial epithelium (secreting polysaccharide rich mucus)
- Plasma cells (secreting large amounts of Ab's)
56
Lysosomal enzymes (acid hydrolases) are initially synthesized in the ER (like all proteins) and then tagged with what in the golgi so they can be sent to the lysosome?
- Mannose-6-phosphate
- Delivered via trans-Golgi vesicles that exprress M6P receptors
57
Describe the steps of fluid-phase pinocytosise/receptor-mediated endocytosis used for lysosomal degradation.
- Plasma membrane wraps around material forms **early endosome**, the **first acidic** compartment encountered
- Then becomes the **late endosome**, where proteolytic enzymes begin digestion; late endosomes mature into lysosomes
58
Large denatured protein complexes and damaged (or senescent) organelles are shuttled into lysosome using what process?
- Autophagy
- Double membrane of ER encircles material and forms an autophagosome, which can then fuse with a lysosome
59
Autophagy is a characteristic sign of \_\_\_\_\_\_\_; what is the hallmark?
- Characteristic sign of **atrophy**
- Hallmark is **decreased protein synthesis**
60
How are microorganisms and/or large fragments of martix and debris able to be degraded by a lysosome?
- Professional phagocytes (macrophages or neutrophils) = **phagocytosis**
- Material is engulfed to form a phagosome that then fuses with lysosome
61
What process is being described?
Lysosomes fuse with endosomes/phagosomes to facilitate degradation of internalized contents
Heterophagy
62
What process involves senescent organelles or denatured proteins targeted for lysosomes-drive degradation by encircling them with a double membrane derived from the ER?
Activated by what?
Marked by what protein?
- Autophagy
- Cell stressors
- LC3 protein
63
What kind of proteins may go though the proteasome degradation pathway?
Tagged by what molecules?
- Cytosolic proteins (TFs or regulatory proteins), senscent proteins, denatured proteins
- Tagged by multiple **ubiquitin** molecules (via E1, E2, and E3 ubiquitin ligases)
64
High levels of misfolded proteins within the ER triggers what?
Leads to what?
- Unfolded protein response
- Reduction in protein synthesis and increase in chaperone proteins to aid in refolding
65
How do mitochondria initiate protein synthesis, with what?
Why is this significant for treatment of disease?
- N-formylmethionine
- Target for antibacterial antibiotics (leaves human translation alone)
66
What is it called when rapidly growing cells upregulate glucose and glutamine uptake but decrease their production of ATP per glucose molecule?
Why does this happen and hallmark for what?
- Warburg effect
- Intermediates that prime TCA cycle are given back to the cell for building instead of producing energy
- Hallmark of cancerous cells
67
What methods of transmission are possible for mitochondrial diseases and why?
- X-linked, autosomal, or maternally inherited
- Constituents of mitochondria derive from both nuclear and mitochondrial genetic transcription
68
Where is Cytochrome C located and why is its release significant?
- Inner mitochondrial membrane
- Release to the cytosol indicates **extensive cellular damage** and triggers the intrinsic/mitochondrial pathway of **apoptosis**
69
Hypoxia, toxic injury, or even mitochondrial aging can lead to significantly increased levels of?
- Reactive oxygen species (i.e., oxygen free radicals and hydrogen peroxide)
- Increases intracellular oxidative stress
70
Wnt binds Frizzled and regulates intracellular levels of what?
The stabilized pool is able to do what?
- Beta-catenin by recruiting (**Disheveled**) protein **inhibiting** Ubiquitin targeting of beta-catenin
- Translocates to the nucleus and form a transcriptional complex
- **Beta-catenin** can serve as a **transcription factor**
71
Signaling from a Tyr kinase-based receptor involves the activation of RAS via GTP binding. What 2 downstream effects does RAS have?
(Give the both whole pathways)
- Activates RAF -\> MAPK -\> activates transcription w/MYC protein and there is cell cycle progression
Or
- Activates PI3K -\> Akt -\> mTOR -\> activates transcription in same way
72
Cell signaling contact with the ECM is mediated through?
Integrins and hemidesmosomes
73
Regardless of the nature of an extracellular stimulus (paracrine, synaptic, or endocrine), the signal it conveys is transmitted to the cell via?
A **specific receptor**
74
What is one example of a signaling ligand diffusing into an adjacent cell and what is its MOA?
- NO
- Activates guanylyl cyclase to generate cGMP ---\> Vasodilation
75
What are the 2 cell surface receptor actions that are typically associated with cell proliferation?
1) G proteins (activation of GTP-binding regulatory protein)
2) RTK's
76
What are the cell surface receptor actions that are typically associated with regulating normal development?
- Proteolytic events or changes in protein binding/stability that activates a latent transcription factor
- Like Notch, Wnt, and Hedgehog
77
Receptors for insulin (as well as IGF-1 and IGF-2), epidermal growth factor (EGF), and platelet derived growth factor (PDGF) are examples of what kind of receptor?
RTKs
78
What is the active vs. inactive form of Ras?
How do mutations affect this process?
- Ras-GTP = **active**
- Ras-GDP = **inactive**
\*Mutations in RAS may lead to **delayed GTP hydrolysis** causing **increased prolierative signaling**
79
What are examples of nonreceptor tyrosine kinases (Src-family kinases) and describe their catalytic activity?
- Immune receptors, some cytokine receptors, and integrins
- Possess **no intrinsic catalytic activity**
80
What serves as the prototype for Src-family kinases (nonreceptor tyrosine kinases)?
Contains which 2 unique functional regions and desrcibe how each works?
- Rous sarcoma virus (SRC)
- **SH2** domains bind receptors phosphorylated by another kinase, allows for aggregation of multiple enzymes
- **SH3** domains mediate other protein-protein interactions, often involving **proline-rich** domains
81
What are transcription factors that regulate the expression of genes that lead to growth and those that lead to growth arrest?
- MYC and JUN are needed for **growth - cell proliferation**
- p53 is needed for the **arrest of growth - cell cycle arrest**
82
Which proteins act as co-receptors in the Wnt/Frizzled signaling pathway?
Lrp5/Lrp6, LDL receptor related proteins 5 and 6
83
Many growth factor pathway genes are \_\_\_\_\_\_\_\_\_\_; gain of function mutations in these genes can convert to them to \_\_\_\_\_\_\_\_\_?
- Proto-oncogenes
- Converted to oncogenes, capable of driving rampant cell proliferation and tumor formation
84
What are the sources of epidermal growth factor (EGF) and its functions?
**Sources:** activated macrophages, salivary glands, and keratinocytes
**Functions:** mitogenic for keratinocytes and fibroblasts, stimulates keratinocyte migration, stimulates formation of granulation tissue
85
What are the EGF receptors associated with cancers?
- **EGFR1** mutations frequently seen in lung, head, neck, breast, and brain cancers
- **ERBB2** receptors (aka **HER2**) is overexpressed in subset of breast cancers
86
What is the hepatocyte growth factor also known as; what are its functions?
- AKA the **Scatter factor**
- Enhances proliferation of hepatocytes and other epithelial cells
- Acts as a **morphogen** in embryonic development (influences tissue differentiation), increases **cell motility**, and enhances hepatocyte survival
87
What is the receptor for HGF and is seen frequently overexpressed or mutated in what kind of tumors?
- **MET,** has intrinsic tyrosine kinase activity
- Renal and thyroid papillary carcinomas
\* MET inhibitors may be of value for cancer therapy
88
Which growth factor acts as a chemoattractant for neutrophils, macrophages, fibroblasts, and smooth muscle cells?
Platelet derived growth factor (PDGF)
89
Which growth factor comes from mesenchymal cells?
VEGF
90
Which growth factor enhances proliferation of hepatocytes and other epithelial cells, increases cell motility?
HGF (scatter factor)
91
Which growth factor stimulates keratinocyte migration, proliferation, and differentiation?
Comes from where?
- KGF (AKA FGF-7)
- Fibroblasts
92
Which growth factor stimulates proliferation of endothelial cells and increases vascular permeability?
VEGF
93
Which growth factor is chemotactic for neutrophils, macrophages, smooth muscle cells, fibroblasts and stimulates proliferation of fibroblasts, endothelial cells, and stimulates ECM protein synthesis?
PDGF
94
What is the major angiogenic factor (inducing blood vessel developement) after injury and in tumors?
What other growth factor helps?
**VEGF-A** (generally referred to as just VEGF) and **bFGF** helps out
95
VEGF-B and PIGF are involved in what?
Embryonic vessel development
96
Which growth factor is chemotactic for leukocytes and fibroblasts, stimulates ECM protein synthesis, and suppresses acute inflammation?
TGF-B
97
Which growth factor is chemotactic and mitogenic for fibroblasts, stimulates angiogenesis and ECM protein synthesis?
FGFs
98
Which growth factor is mitogenic for keratinocytes and fibroblasts, stimulates keratinocyte migration, and stimulates formation of granulation tissue?
EGF
99
There are 2 types of fibroblast growth factor, which is basic and which is acidic?
FGF-1 = **acidic**
FGF-2 = **basic**
100
Which growth factor stimulates proliferation of hepatocytes and other epithelial cells?
TGF-alpha
101
What is the most important inducer of VEGF, through what pathways?
What are 2 other inducers?
- Hypoxia via **HIF-1**
- Other inducers include PDGF and TNF-alpha (produced at sites of inflammation or wound healing)
102
Antibodies against which growth factor are approved for the tx of renal and colon cancers since they require angiogenesis for their spread and growth?
VEGF
103
Anti-VEGF antibodies are used in treatment of which diseases?
Opthalmic diseases including "wet" AMD
104
Increased levels of _________ in pregnant women may cause preeclampsia; how?
- **Soluble** version VEGFR-1 (**s-FLT-1**)
- By "sopping up" the free VEGF required for maintaining normal endothelium
105
Which growth factor inhbits MMPs, stimulates production of collagen, fibronectin, and proteoglycans, suppresses inflammation, and leads to scars and fibrosis in lung, liver, and kidneys?
TGF-B
106
What does the ECM provide that's important in tissue repair?
- Scaffolding
- Ability to restore normal architecture of an organ, such as the liver, depends on the viability of the supporting CT framework
107
Which VEGF receptors is found in the endothelium and is the most important for angiogenesis?
What type of receptor are VEGF receptors?
- VEGFR 2
- Receptor Tyrosine Kinases!
108
What synthesizes the interstitial matrix and what are its major constituents?
- Synthesized by **mesenchymal cells (i.e., fibroblasts)**
- Major constituents are **fibrillar** and **nonfibrillar collagens**, as well as **fibronectin, elastin, proteoglycans,** and **hyaluronate**
109
What are the major constituents of the Basement Membrane?
- Amorphous **nonfibrillar type IV collagen** and **LAMININ**
- Also contains proteoglycans
110
The components of the ECM fall into three groups, what are they?
1) Fibrous structural proteins - collagens and elastins (**tensile strength/recoil**)
2) Water-hydrated gels - proteoglycans and hyaluronan (**compressive resistance** and **lubrication**)
3) Adhesive glycoproteins
111
What are the fibrous structural proteins?
What do they confer?
Cross linked by what enzyme?
- Collagens and elastin
- Tensile strength and recoil
- Lysyl oxidase
112
Lysyl oxidase requires what?
Without it there what will result?
- Vitamin C
- Easy bleeding and poor healing
113
Elastins are important in what structures?
- Cardiac valves and large blood vessels
- Allows tissues to recoil and recover shape after deformation
114
What kind of defects lead to weakened aortic walls?
What associated syndrome?
- Fibrillin (component of Elastic fibers)
- Marfan syndrome
115
What forms highly compressible gels that confer resistance to compressive forces and provides lubrication in joint cartilages?
Proteoglycans and hyaluronan
116
What provides the scaffolding for subsequent ECM deposition, angiogenesis, and reepithelialization in healing wounds?
Fibronectin
117
Which CDKIs inhibit all CDKs?
**p21** (CDKN1A), **p27** (CDKN1B), and **p57** (CDKN1C)
118
What are the Cyclin-CDK regulators of G1 to S (3 of them)?
How do they regulate?
What is monitored here?
- D-CDK4 and D-CDK6
- E-CDK2
- Regulation by **phosphorylating** the **Rb protein (pRb)**
- Integrity of the DNA
119
What INK4 inhibitors will act on D-CDK4 and D-CDK6?
- p15 (CDKN2**B**), p16 (CDKN2**A**), p18 (CDKN2**C**), p19 (CDKN2**D**)
- Inhibit CDK4 and CDK6 which are involved in the G1/S transition
120
The S phase requires what cyclins and CDK's to be active?
A-CDK2 and A-CDK1
121
The G2 to M transition requires what cyclin/CDK?
What is checked here?
- B-CDK1
- Makes sure the DNA was successfully duplicated
122
What are the fibrillar collagens and where are they found?
- Types I, II, III, V
- Found in bone, tendon, cartilage, blood vessels, skin, and scars
123
Genetic defects in fibrillar collagen causes what 2 diseases?
1) Osteogenesis imperfecta
2) Ehlers-Danlos syndrome
124
What are the 3 Non-fibrillar collagens and what is each associated with?
- Type IV: form planar basement membranes
- Type IX: regulate collagen diameters via FACITs
- Type VII: anchoring fibrils to basement membranes
125
Besides providing compressibility to tissues, what serves as a reservoir for growth factors secreted into the ECM (i.e., FGF and HGF)?
Proteoglycans
126
Which transmembrane glycoproteins functionally and structurally link the intracellular cytoskeleton with the outside world (ECM)?
Integrins
127
What found on the surface of leukocytes is essential in mediating firm adhesions and transmigration across endothelium at sites of inflammation?
**Integrins == adhesion**
128
What are labile cells and stable cells, give examples of each?
**Labile**: continously cycling (i.e., epidermis, GIT)
**Stable:** quiescent but can enter the cell cycle under right conditions (i.e., hepatocytes)
129
If DNA repair mechanisms are unable to work due to the genetic derrangement being too severe for repair what are the 2 options?
1) Cell will undergo apoptosis
2) Enter a nonreplicative state called **senescense**, primarily through p53-dependent mechanisms
130
What are senescent cells and how are they related to cancer?
- Cell that under no circumstances can enter the cell cycle
- Hallmark of cancer = loss of replicative senescence
131
What type of DNA variation is bi-allelic, involves gene-coding sequences and may be responsible for phenotypic differences?
CNV (copy # variation)
132
What are mesenchymal stem cells?
- **Multipotent** cells found in the **bone marrow**
- Differentiate into a variety of ***stromal cells***: chondrocytes, osteocytes, adipocytes, and myocytes
133
Ligands binding to *Notch* receptors leads to?
- Proteolytic cleavage of the receptor an subsequent nuclear translocation of the cytoplasmic piece (intracellular Notch) to form a transcription complex
- **Transcription of the notch target gene**
134
While most interest historically has been focused on binding of transcription factors to gene promoters, it is now widely appreciated that most transcription factors bind widely throughout genomes, with the majority of binding occuring?
In **long-range regulatory** elements such as **enhancers**
135
For a transcription factor to induce transcription, it must also possess what type of interaction domains?
What are these domains responsible for recruiting (what is most important)?
- **Protein:protein** interaction domains
- Directly or indirectly recruit **histone modifying enzymes, chromatin remodeling complexes, and (MOST IMPORTANTLY) RNA POLYMERASE!**
136
GFs are also important in driving a host of nongrowth activities as well, such as?
Migration
Differentiation
Synthetic capacity
137
HGF (AKA scatter factor) has mitogenic effects on which cells and in which location?
- Hepatocytes
- Epithelial cells: biliary, pulmonary, renal, mammary, and epidermal
138
HGF is synthesized as an inactive precursor (pro-HGF), how is it activated (which AA/enzyme involved)?
Proteolytically activated by **serine** **proteases** released at **site of injury**
139
Which GF induces fibroblast, endothelial, and smooth muscle cell proliferation and **matrix synthesis**, and is chemotactic for these cells (and inflammatory cells)?
PDGF
140
Placental growth factor (PIGF) is a homodimeric protein in the same family as what other important GF?
Which part of this family specifically?
- VEGF
- VEGF-B and PIGF are involved in embryonic vessel development
141
VEGF-C and VEGF-D stimulate what?
Both angiogenesis and lymphatic development **(*lymphangiogenesis*)**
142
VEGFs are also involved in the maintenance of normal adult endothelium (i.e., not involved in angiogenesis), with the highest expression in epithelial cells adjacent to?
Where is this epithelium found?
- Fenestrated epithelium
- Podocytes in kidney
- Pigment epithelium in retina
- Choroid plexus in brain
143
Releaed FGFs associate with ________ in the extracellular matrix, which serves as a reservoir for inactive factors which can be subsequently released by proteolysis (i.e., at site of wound healing)
- Heparan sulfate
- Especially **bFGF**
144
There are 2 TGF-B receptors (types I and II), both with what type of activity?
Induce phosphorylation of a variety of downstream cytoplasmic transcription factors called?
Once phosphorylated these transcription factors form heterodimers with?
- Serine/threonine kinase activity
- *Smads*
- Heterodimers with **Smad4**
145
TGF-B has multiple and often opposing effects depending on the tissue and concurrent signals. Agents with such multiplicity of effects are called?
Pleiotropic
146
How does TGF-B inhibit collagen degradation?
- Decreases MMP activity
- Increasing activity of **tissue inhibitors of proteinases (TIMPs)**
147
The ECM occurs in 2 basic forms, what are they?
Where is each found and the major constituents of each?
1) **Interstitial matrix**: spaces between cells in the CT and between parenchymal epithelium and the underlying supportive vascular and smooth muscle structures
- **Major constituents:** fibrillar and non-fibrillar collagens, fibronectic, elastin, proteoglycans, hyaluronate.
2) **Basement membrane**: random array of interstitial matrix in CT, that becomes highly organized around epithelial cells, endothelial cells, and smooth muscle cells
- **Major constituents:** nonfibrillar collagen type IV and laminin
148
Interaction of ECM and GFs mediated cell signaling occurs via cell surface integrins that interact w/ cytoskeleton at focal adhesion complexes, which are protein aggregates that include which linking molecules?
Vinculin
Talin
α-actinin
149
What binds bFGF released from damaged ECM, and facilitates a concentrated interaction between bFGF-heparan sulfate complex and the FGF receptor?
Syndecan
150
What is the function of the highly negative charged sulfated sugars on the proteoglycan "bristles"?
- Recruits **Na+** and **water**
- Generates a **viscous, but compressible matrix**
151
After secretion, collagen achieves lateral stability through collagen cross-linking involving which enzyme?
Lysyl oxidase
152
What is the most abundant glycoprotein in the basement membrane and its functions?
- Laminin
- Connects cells to underlying ECM components such as type IV collagen and heparan sulfate (mediates attachement to basement membrane)
- Also can modulate cell proliferation, differentiation, and motility
153
Fibronectin can bind to ECM and to integrins, in binding to integrins what AA motif is used?
Arginine-glycine-aspartic acid (RGD) motifs
