Signaling Pathways and Development Flashcards
1
Q
What are two unique signaling pathways regulated by proteolysis?
-play crucial roles in embryonic development
A
Hedgehog pathway (Hh) and Wnt pathway
2
Q
Involved in maintaining stem cell niches in various tissues, including CNS, skin, and gut
A
Hh and Wnt
3
Q
The Hh and Wnt pathways have been implicated in
A
Cancer and tissue repair
4
Q
Diseases resulting from defects in Hh or Wnt can be either
A
- ) Congenital (inherited defects)
2. ) Sporadic (Somatic mutations)
5
Q
What are the three members of the Hedgehog family?
A
- ) Indian
- ) Sonic
- ) Desert
6
Q
Necessary for the development of cartilage and bone
A
Indian Hh (Ihh)
7
Q
Necessary for the development of the central nervous system
A
Sonic Hh (Shh)
8
Q
Important in the development of peripheral nerves
A
Desert Hh (Dhh)
9
Q
What are the core components of the Hh pathway?
A
- ) Hedgehog
- ) Patched (Ptc) receptor
- ) Smoothened (Smo)
- ) Gli/Ci proteins
- ) PKA
10
Q
The hedgehogs are actually
A
Ligands
11
Q
Secreted hydrophobic proteins produced and secreted by localized groups of cells in both embryos and adults
A
Hedgehog (Shh, Ihh, and Dhh)
12
Q
12-span transmembrane protein with homology to bacterial proton-driven transmembrane molecular transporters
-binds Hh ligands
A
Patched (Ptc) receptor
13
Q
7-α-helix G-protein-coupled transmembrane protein
-Does not bind Hh
A
Smoothened (Smo)
14
Q
Does the patched receptor bind Hedgehog?
A
Yes
15
Q
Does the smoothened receptor bind Hedgehog?
A
No
16
Q
Transcription factors that can either activate or repress target gene expression depending on signaling status
A
Gli/Ci proteins
17
Q
Phosphorylates Gli/Ci proteins to target them for proteolysis in the proteosome
A
Protein Kinase A (PKA)
18
Q
Partially proteolyzed protein that acts as a transcription REPRESSOR
A
GliREP (Ci75)
19
Q
Full-length protein that functions as a transcriptional ACTIVATOR
A
GliACT (Ci155)
20
Q
Ptc not bound to Hedgehog acts as an
A
Inhibitor
21
Q
Ptc bound to Hedgehog acts as a
A
Receptor
22
Q
Sonic hedgehog transduction components localize to the
A
Primary Cilium
23
Q
Non-motile cilium that occurs singly on most cells in the vertebrate body
-critical sensors of extracellular information
A
Primary Cilium
24
Q
Numerous cilia proteins are involved in
A
Hh signaling
25
Localize signal transduction components
Cilia
26
Humans with ciliary defects can have problems with
Vision, Hearing, Smell, Left-right organ location (Situs Inversus), Kidney functions, and Hh signaling
27
Congenital (inherited) human disorders of Hh signaling primarily affects the
Limb and CNS
28
Localized to "organizing centers" in the limb buds and early CNS
Sonic Hedgehog (Shh)
29
The ZPA morphogen
Sonic hedgehog
30
Sonic Hedgehog controls digit pattern by graded inhibition of
Gli3 proteolysis
31
Sonic hedgehog is required to inhibit the formation of
Gli3REP
32
Defects in this ligand lead to decreased production of Dentate Gyrus Granule Cells (a CNS stem cell)
Sonic Hedgehog
33
The product of over-proliferation of embryonic CNS progenitor ("stem") cells, indicating a link between Hh signaling and stem cell proliferation/maintenance
Exencephaly
34
In the adult CNS, stimulating neurogenesis in resident stem cells may be of value in disorders including
Alzheimer's, Parkinson's disease, and Stroke
35
The congenital diseases related to abnormal Hh signaling can be grouped by effect on
Hh pathway
36
Can result from mutations in positive transduction pathway components
Diseases associated with reduced Hh signaling
37
Diseases associated with reduced Hh signaling are associated with increased
Gli3REP activity
38
An example of a disease associated with reduced Hh signaling is
Holoprosencephaly (HPE)
39
A developmental disorder mainly characterized by incomplete midline formation during forebrain development
Holoprosencephaly (HPE)
40
What is the incidence of holoprosencephaly?
4-8/100,000
41
One of the most severe presentations of Holoprosencephaly (HPE) is
Cyclopia
42
What are the traits shown in mice with Sonic Hedgehog knockout?
Cyclopia/holoprosencephaly and limb defects
43
In HPE, pathogenesis is thought to result from
Shh protein haploinsufficiency
44
When a single copy of a gene is not sufficient for normal function
Haploinsufficiency
45
In cases resulting from Shh haploinsufficiency, the phenotype is limited to
-indicates that the developing structures likely have different sensitivities to reduced gene dosage
Brain/face defects (not other tissues)
46
Have been found in both familial and sporadic cases of holoproencephaly
Mutations in Shh and Gli2
47
HPE is caused by mutations that result in
Reduced Shh signaling
48
Acts very similarly to mutations that result in reduced Hh signaling
Mutations that bock Smoothened (Smo) activation
49
Inhibits Smo and results in HPE
Cyclopamine
50
A 7-α-helix G-protein coupled transmembrane protein and a central component of the Hh signaling pathway
Smoothened (Smo)
51
Not actually a receptor for Hh proteins
Smo
52
Presents an attractive "druggable" target for manipulating Hh signaling in pathogenic conditions
Smo
53
What are two natural compounds that antagonize Smo?
Cyclopamine and Jervine
54
Mature Hh protein is generated from a longer precursor that undergoes a self-cleavage reaction that requires the addition of
Cholesterol
55
The processed form of the protein containing a covalent cholesterol adduct is the
Active signalling species
56
Mutations in the Shh gene in either the signaling domain or autocatalytic cleavage and cholesterol transferase domain will both cause
Holoproencephaly
57
A prominent constituent of animal cells membranes, comprising up to 30% of the plasma membrane lipid content in some tissues
Cholesterol
58
The first step of cholesterol synthesis requires
Acetyl CoA
59
Which enzyme catalyzes the final step of cholesterol biosynthesis?
delta-7-reductase (DHCR7)
60
Loss-of-function mutations for the sterol delta-7-reductase (DHCR7) gene are associated with
Smith-Lemli-Opitz Syndrome and HPE
61
Encodes and enzyme that is critical in cholesterol synthesis
DHCR7 gene
62
Cholesterol-reducing drugs in the group known as HMG-CoA reductase inhibitors should not be taken by women who are pregnant of who plan to become pregnant soon because they can cause
HPE
63
What are two types of diseases that can result from increased or unregulated Hh signaling?
Congenital defects and cancer
64
Can result from mutations in negative transduction pathway components
Increased or unregulated Hh signaling
65
What is one potential way to treat increased or unregulated Hh signaling?
Cyclopamine or other Smo inhibitors
66
Mutations that result in increased or unregulated Hh signaling lead to loss of
Gli3REP
67
Mutations in GLI3 lead to loss of Gli3REP and are linked to which three related autosomal dominant syndromes that show limb and brain defects?
1. ) Greig Cephalopolysyndactyly Syndrome (GCPS)
2. ) Pallister-Hall Syndrome
3. ) Postaxial Poydactyly Syndrome (PPS)
68
Postaxial Polydactyly (PPS) results from
GLI3 haploinsufficiency
69
A tumor arrising in the cerebellum during development
Medulloblastoma
70
The most common malignant brain tumor in children
Medulloblastoma
71
Medulloblastoma arises from granule neuron progenitors (GNPs) from the
Rhombic Lip
72
In Medulloblastoma, there is a loss of function in
PTCH1
73
Ptc1 +/- heterozygous mice have a 15-43% incidence of
Medulloblastoma
74
Nevoid Basal Cell Carcinoma (skin cancer) patients (aka Gorlin Syndrome) that have mutations in PTCH1 have a 3-5% incidence of
Medulloblastoma
75
Gene profiling of medulloblastoma shows an amplification of which Hh pathway proteins?
GLI1 and GLI2
76
Medulloblastoma is an example of a disease which has shown
Drug resistence
77
All tumor cells begin as a single abnormal cell. As the tumor cells grow in size, they accumulate additional mutations that increase
Malignancy
78
Complicates tumor therapy
Genetic heterogeneity
79
Can occur during tumor treatment
Clonal selection
80
What are the two pathways for Wnt signaling?
Canonical and non-canonical
81
The non-canonical pathway does not involve
β-catenin
82
The Wnt ligand binds to the co-receptors
Frizzled/Frz and Arrow/Lrp
83
When the Wnt ligand binds to the co-receptors Frizzled/Frz and Arrow/Lrp, the destruction complex is dissociated, interrupting
β-catenin phosphorylation
84
Unphosphorylated β-catenin then enters the nucleus and binds
Tcf/Lef proteins
85
Turns on gene expression
β-catenin binding to Tcf/Lef
86
What do Tcf/Lef associate with in that absence of β-
| catenin phosphorylation to block target gene expression?
Groucho/Grg co-factors
87
Bi-functional transcription factors
Tcf/Lef proteins
88
What are the two intracellular pools of β-catenin
1. ) Cytoplasmic
| 2. ) Cell membrane
89
Involved in signaling and regulate gene expression
Cytoplasmic β-catenin
90
Involved in cell adhesion/tissue homeostasis
-Associated with cadherins/adherins
Cell membrane β-catenin
91
Phosphorylates β-catenin in the absence of Wnt signaling
"Destruction complex" (Axin, APC, and Gsk3)
92
Phosphorylated β-catenin is degraded by
β-TrCP
93
Further removes pgroups from β-catenin, leading
| to itʼs stabilization
PP2A
94
Can be altered by changes in β-catenin alone
Wnt Signaling
95
Mutations in β-catenin that prevent phosphorylation promote stability and result in
Constitutive pathway action
96
Strongly linked to colorectal cancer in FAP (famililal adenomatous polyposis)
APC (adenomatous polyposis coli) mutations
97
Wnt and frat are both classified as
Proto-oncogenes
98
What are three tumor suppressors in Wnt signaling pathway?
Axin, APC, and Tcf1
