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BMS > Signaling Pathways and Development > Flashcards

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

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2
Q

Involved in maintaining stem cell niches in various tissues, including CNS, skin, and gut

A

Hh and Wnt

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3
Q

The Hh and Wnt pathways have been implicated in

A

Cancer and tissue repair

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4
Q

Diseases resulting from defects in Hh or Wnt can be either

A
  1. ) Congenital (inherited defects)

2. ) Sporadic (Somatic mutations)

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5
Q

What are the three members of the Hedgehog family?

A
  1. ) Indian
  2. ) Sonic
  3. ) Desert
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6
Q

Necessary for the development of cartilage and bone

A

Indian Hh (Ihh)

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7
Q

Necessary for the development of the central nervous system

A

Sonic Hh (Shh)

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8
Q

Important in the development of peripheral nerves

A

Desert Hh (Dhh)

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9
Q

What are the core components of the Hh pathway?

A
  1. ) Hedgehog
  2. ) Patched (Ptc) receptor
  3. ) Smoothened (Smo)
  4. ) Gli/Ci proteins
  5. ) PKA
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10
Q

The hedgehogs are actually

A

Ligands

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11
Q

Secreted hydrophobic proteins produced and secreted by localized groups of cells in both embryos and adults

A

Hedgehog (Shh, Ihh, and Dhh)

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12
Q

12-span transmembrane protein with homology to bacterial proton-driven transmembrane molecular transporters

-binds Hh ligands

A

Patched (Ptc) receptor

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13
Q

7-α-helix G-protein-coupled transmembrane protein

-Does not bind Hh

A

Smoothened (Smo)

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14
Q

Does the patched receptor bind Hedgehog?

A

Yes

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15
Q

Does the smoothened receptor bind Hedgehog?

A

No

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16
Q

Transcription factors that can either activate or repress target gene expression depending on signaling status

A

Gli/Ci proteins

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17
Q

Phosphorylates Gli/Ci proteins to target them for proteolysis in the proteosome

A

Protein Kinase A (PKA)

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18
Q

Partially proteolyzed protein that acts as a transcription REPRESSOR

A

GliREP (Ci75)

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19
Q

Full-length protein that functions as a transcriptional ACTIVATOR

A

GliACT (Ci155)

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20
Q

Ptc not bound to Hedgehog acts as an

A

Inhibitor

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21
Q

Ptc bound to Hedgehog acts as a

A

Receptor

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22
Q

Sonic hedgehog transduction components localize to the

A

Primary Cilium

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23
Q

Non-motile cilium that occurs singly on most cells in the vertebrate body

-critical sensors of extracellular information

A

Primary Cilium

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24
Q

Numerous cilia proteins are involved in

A

Hh signaling

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25
Q

Localize signal transduction components

A

Cilia

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26
Q

Humans with ciliary defects can have problems with

A

Vision, Hearing, Smell, Left-right organ location (Situs Inversus), Kidney functions, and Hh signaling

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27
Q

Congenital (inherited) human disorders of Hh signaling primarily affects the

A

Limb and CNS

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28
Q

Localized to “organizing centers” in the limb buds and early CNS

A

Sonic Hedgehog (Shh)

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29
Q

The ZPA morphogen

A

Sonic hedgehog

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30
Q

Sonic Hedgehog controls digit pattern by graded inhibition of

A

Gli3 proteolysis

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31
Q

Sonic hedgehog is required to inhibit the formation of

A

Gli3REP

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32
Q

Defects in this ligand lead to decreased production of Dentate Gyrus Granule Cells (a CNS stem cell)

A

Sonic Hedgehog

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33
Q

The product of over-proliferation of embryonic CNS progenitor (“stem”) cells, indicating a link between Hh signaling and stem cell proliferation/maintenance

A

Exencephaly

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34
Q

In the adult CNS, stimulating neurogenesis in resident stem cells may be of value in disorders including

A

Alzheimer’s, Parkinson’s disease, and Stroke

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35
Q

The congenital diseases related to abnormal Hh signaling can be grouped by effect on

A

Hh pathway

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36
Q

Can result from mutations in positive transduction pathway components

A

Diseases associated with reduced Hh signaling

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37
Q

Diseases associated with reduced Hh signaling are associated with increased

A

Gli3REP activity

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38
Q

An example of a disease associated with reduced Hh signaling is

A

Holoprosencephaly (HPE)

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39
Q

A developmental disorder mainly characterized by incomplete midline formation during forebrain development

A

Holoprosencephaly (HPE)

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40
Q

What is the incidence of holoprosencephaly?

A

4-8/100,000

41
Q

One of the most severe presentations of Holoprosencephaly (HPE) is

42
Q

What are the traits shown in mice with Sonic Hedgehog knockout?

A

Cyclopia/holoprosencephaly and limb defects

43
Q

In HPE, pathogenesis is thought to result from

A

Shh protein haploinsufficiency

44
Q

When a single copy of a gene is not sufficient for normal function

A

Haploinsufficiency

45
Q

In cases resulting from Shh haploinsufficiency, the phenotype is limited to

-indicates that the developing structures likely have different sensitivities to reduced gene dosage

A

Brain/face defects (not other tissues)

46
Q

Have been found in both familial and sporadic cases of holoproencephaly

A

Mutations in Shh and Gli2

47
Q

HPE is caused by mutations that result in

A

Reduced Shh signaling

48
Q

Acts very similarly to mutations that result in reduced Hh signaling

A

Mutations that bock Smoothened (Smo) activation

49
Q

Inhibits Smo and results in HPE

A

Cyclopamine

50
Q

A 7-α-helix G-protein coupled transmembrane protein and a central component of the Hh signaling pathway

A

Smoothened (Smo)

51
Q

Not actually a receptor for Hh proteins

52
Q

Presents an attractive “druggable” target for manipulating Hh signaling in pathogenic conditions

53
Q

What are two natural compounds that antagonize Smo?

A

Cyclopamine and Jervine

54
Q

Mature Hh protein is generated from a longer precursor that undergoes a self-cleavage reaction that requires the addition of

A

Cholesterol

55
Q

The processed form of the protein containing a covalent cholesterol adduct is the

A

Active signalling species

56
Q

Mutations in the Shh gene in either the signaling domain or autocatalytic cleavage and cholesterol transferase domain will both cause

A

Holoproencephaly

57
Q

A prominent constituent of animal cells membranes, comprising up to 30% of the plasma membrane lipid content in some tissues

A

Cholesterol

58
Q

The first step of cholesterol synthesis requires

A

Acetyl CoA

59
Q

Which enzyme catalyzes the final step of cholesterol biosynthesis?

A

delta-7-reductase (DHCR7)

60
Q

Loss-of-function mutations for the sterol delta-7-reductase (DHCR7) gene are associated with

A

Smith-Lemli-Opitz Syndrome and HPE

61
Q

Encodes and enzyme that is critical in cholesterol synthesis

A

DHCR7 gene

62
Q

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

63
Q

What are two types of diseases that can result from increased or unregulated Hh signaling?

A

Congenital defects and cancer

64
Q

Can result from mutations in negative transduction pathway components

A

Increased or unregulated Hh signaling

65
Q

What is one potential way to treat increased or unregulated Hh signaling?

A

Cyclopamine or other Smo inhibitors

66
Q

Mutations that result in increased or unregulated Hh signaling lead to loss of

67
Q

Mutations in GLI3 lead to loss of Gli3REP and are linked to which three related autosomal dominant syndromes that show limb and brain defects?

A
  1. ) Greig Cephalopolysyndactyly Syndrome (GCPS)
  2. ) Pallister-Hall Syndrome
  3. ) Postaxial Poydactyly Syndrome (PPS)
68
Q

Postaxial Polydactyly (PPS) results from

A

GLI3 haploinsufficiency

69
Q

A tumor arrising in the cerebellum during development

A

Medulloblastoma

70
Q

The most common malignant brain tumor in children

A

Medulloblastoma

71
Q

Medulloblastoma arises from granule neuron progenitors (GNPs) from the

A

Rhombic Lip

72
Q

In Medulloblastoma, there is a loss of function in

73
Q

Ptc1 +/- heterozygous mice have a 15-43% incidence of

A

Medulloblastoma

74
Q

Nevoid Basal Cell Carcinoma (skin cancer) patients (aka Gorlin Syndrome) that have mutations in PTCH1 have a 3-5% incidence of

A

Medulloblastoma

75
Q

Gene profiling of medulloblastoma shows an amplification of which Hh pathway proteins?

A

GLI1 and GLI2

76
Q

Medulloblastoma is an example of a disease which has shown

A

Drug resistence

77
Q

All tumor cells begin as a single abnormal cell. As the tumor cells grow in size, they accumulate additional mutations that increase

A

Malignancy

78
Q

Complicates tumor therapy

A

Genetic heterogeneity

79
Q

Can occur during tumor treatment

A

Clonal selection

80
Q

What are the two pathways for Wnt signaling?

A

Canonical and non-canonical

81
Q

The non-canonical pathway does not involve

A

β-catenin

82
Q

The Wnt ligand binds to the co-receptors

A

Frizzled/Frz and Arrow/Lrp

83
Q

When the Wnt ligand binds to the co-receptors Frizzled/Frz and Arrow/Lrp, the destruction complex is dissociated, interrupting

A

β-catenin phosphorylation

84
Q

Unphosphorylated β-catenin then enters the nucleus and binds

A

Tcf/Lef proteins

85
Q

Turns on gene expression

A

β-catenin binding to Tcf/Lef

86
Q

What do Tcf/Lef associate with in that absence of β-

catenin phosphorylation to block target gene expression?

A

Groucho/Grg co-factors

87
Q

Bi-functional transcription factors

A

Tcf/Lef proteins

88
Q

What are the two intracellular pools of β-catenin

A
  1. ) Cytoplasmic

2. ) Cell membrane

89
Q

Involved in signaling and regulate gene expression

A

Cytoplasmic β-catenin

90
Q

Involved in cell adhesion/tissue homeostasis

-Associated with cadherins/adherins

A

Cell membrane β-catenin

91
Q

Phosphorylates β-catenin in the absence of Wnt signaling

A

“Destruction complex” (Axin, APC, and Gsk3)

92
Q

Phosphorylated β-catenin is degraded by

93
Q

Further removes pgroups from β-catenin, leading

to itʼs stabilization

94
Q

Can be altered by changes in β-catenin alone

A

Wnt Signaling

95
Q

Mutations in β-catenin that prevent phosphorylation promote stability and result in

A

Constitutive pathway action

96
Q

Strongly linked to colorectal cancer in FAP (famililal adenomatous polyposis)

A

APC (adenomatous polyposis coli) mutations

97
Q

Wnt and frat are both classified as

A

Proto-oncogenes

98
Q

What are three tumor suppressors in Wnt signaling pathway?

A

Axin, APC, and Tcf1

BMS (62 decks)

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