Module 5: Cell Signaling: 4 Alternative Signaling Routes in Gene Regulation Flashcards
What do extracellular signaling molecules often change to carry out their effects?
Gene expression
How do extracellular signaling molecules initiate changes in gene expression?
By initiating signaling pathways that change the activities of transcription regulators
What is a less common mechanism for controlling gene expression?
Pathways that depend on regulated proteolysis.
How can gene expression be controlled in relation to the daily cycle?
By the circadian rhythm
Name one mechanism that controls the activity and location of latent transcription regulators.*
Regulated proteolysis
The daily cycle of light and dark that influences gene expression.
circadian rhythm?
Control cell-fate choices, regulating pattern formation, and continual tissue renewal.
Notch receptor protein
In which process is the Notch receptor protein best known to play a role?
Production of Drosophila neural cells.
What happens when a precursor cell commits to becoming a neural cell in Drosophila?
It signals to its immediate neighbors **not to become neural cells.
What is the mechanism called where a neural precursor inhibits neighboring cells from becoming neural cells?
Lateral inhibition
What type of signaling mechanism does lateral inhibition depend on?
Contact-dependent signaling
What signal protein is involved in lateral inhibition where it binds to notch receptor protein?
Delta
What does Delta bind to during lateral inhibition?
Notch receptor protein
What happens when the Notch signaling process is defective?*
excess of neural cells is **produced **at the expense of epidermal cells, which can be lethal.
What happens to the neighboring cells that are inhibited during lateral inhibition?*
develop into epidermal cells
A single-pass transmembrane protein and latent transcription regulator.
Notch protein
What process is required for Notch to function?
Proteolytic processing
the breakdown of proteins into smaller polypeptides or amino acids*
proteolysis
What are the steps involved in the activation of Notch proteins? (5)
- Delta binds to Notch - Delta, a membrane-bound ligand, binds to the Notch receptor.
- Protease cleaves Notch - A plasma-membrane-bound protease cleaves the cytoplasmic tail of Notch.
- Cytoplasmic tail translocates to the nucleus - The cleaved tail moves into the nucleus.
- Activation of Notch response genes - The tail activates transcription of Notch response genes by binding to a DNA-binding protein.
- Conversion of repressor to activator - The tail transforms the DNA-binding protein from a transcriptional repressor into a transcriptional activator.
What triggers the activation of Notch?
Binding of Delta to Notch
Activation of Notch: What cleaves the cytoplasmic tail of Notch upon activation? Where does the cleaved Notch cytoplasmic tail translocate? (2)
- Plasma-membrane-bound protease
- Into the nucleus
Activation of Notch: What does the Notch cytoplasmic tail activate in the nucleus?
Transcription of Notch-response genes
Activation of Notch: How does the Notch cytoplasmic tail interact with DNA-binding proteins?
it binds to it
Activation of Notch: Notch converts DNA-binding proteins from transcriptional repressors into __.
transcriptional activators
How many proteolytic cleavage steps does the Notch receptor undergo? How many of the cleavage steps depend on Delta binding? (2)
- 3
- 2
What are the three steps involved in the proteolytic cleavage of Notch receptors? What is the final cleavage? (4)
- 1st – normal biosynthesis
- 2nd – binding of Delta to Notch
- 3rd – cutting free the cytoplasmic tail of the activated receptor
- final cleavage - mediated by γ-secretase to release the Notch tail.
Which cleavage step of the Notch receptor occurs during normal biosynthesis?
1st
Where does the first cleavage of Notch occur?*
golgi apparatus
What cleavage step of the Notch receptor occurs in the binding of Delta to the Notch receptor?
2nd
What mediates the second cleavage of Notch?*
extracellular protease
What cleavage step of the Notch receptor occurs when the cytoplasmic tail of the activated receptor releases a Notch?
3rd
What enzyme complex mediates the final cleavage of the Notch tail?
γ-secretase
What condition is associated with mutations in the gene encoding Presenilin (the essential subunit of γ-secretase involved in Notch cleavage)?*
Early-onset familial Alzheimer’s disease
Is Notch activation reversible?*
No
Secreted signal molecules that act as local mediators and morphogens.
Wnt proteins
In which organisms were Wnt proteins independently discovered? (2)
- Drosophila (flies)
- mice
In drosophila, it acts as a morphogen in wing development.
Wingless (Wg) gene
In mice, it promotes the development of breast tumors when activated by a viral integration.
Int1 gene
What are the two main signaling pathways activated by Wnt proteins? (2)
- Wnt/β-catenin pathway
- planar polarity pathway
- A signaling pathway involving β-catenin as a latent transcription regulator.
- involved in regulating the proteolysis of β-catenin
Wnt/β-catenin pathway
A signaling pathway that coordinates the polarization of cells in the plane of a developing epithelium.
planar polarity pathway
What happens to β-catenin in unstimulated cells?*
degraded rapidly
What stabilizes cytoplasmic β-catenin in cells?*
Wnt signaling
Wnt/β-catenin pathway: In cell-cell junctions, what contributes to the control of cell-cell adhesions?
β-catenin
In the Wnt/β-catenin pathway, it binds to β-catenin, keeps it out of the nucleus, and promotes its degradation.
degradation complex
In the Wnt/β-catenin pathway, which two kinases are responsible for phosphorylating β-catenin? (2)
- Casein kinase 1 (CK1)
- glycogen synthase kinase 3 (GSK3)
In the Wnt/β-catenin pathway, which hold the protein degradation complex together? (2)
- axin
- Adenomatous polyposis coli (APC)
What are the two co-receptors that Wnt proteins interact with? (2)
- Frizzled protein
- LDL-receptor-related protein (LRP)
In the Wnt/β-catenin pathway, what proteins are recruited upon activation of the Wnt receptor complex?
Dishevelled scaffold proteins
In the Wnt/β-catenin pathway, which kinases promote the phosphorylation of the LRP receptor? (2)
- Casein kinase 1 (CK1)
- glycogen synthase kinase 3 (GSK3)
In the Wnt/β-catenin pathway, what is brought to the receptor complex and inactivated, disrupting the β-catenin degradation complex?
Axin
In the Wnt/β-catenin pathway, what happens to β-catenin when the degradation complex is disrupted? (2)
- accumulates; and
- translocates to the nucleus
In the Wnt/β-catenin pathway, it alters the pattern of gene transcription.
β-catenin in the nucleus
The composition of the inhibitory complex when there is no Wnt signaling is __ bound to a co-repressor protein of the __.
- LEF1/TCF family proteins
- Groucho family
In the Wnt/β-catenin pathway, it acts as a coactivator, inducing the transcription of Wnt target genes.
β-catenin (when Wnt signaling is present)
In the Wnt/β-catenin pathway, it causes a switch from transcriptional repression to transcriptional activation.
Wnt signaling
Which important regulator of cell growth and proliferation is activated by β-catenin?
Myc
What percentage of human colon cancers involve mutations in the Apc gene?
80%
Mutations in the __ on __ inhibit β-catenin’s ability to bind to Apc, allowing β-catenin to __ in the __.
- Apc gene
- β-catenin
- accumulate
- nucleus
When β-catenin accumulates in the nucleus, it stimulates the transcription of __ and other __.
- c-Myc
- Wnt target genes
The wnt/β-catenin pathway contributes to cancer development due to uncontrolled cell growth and proliferation due to the activation of __, even in the absence of __.
- target genes
- Wnt signaling
Secreted signal molecules that act as local mediators and morphogens.
hedgehog proteins
Hedgehog proteins activate latent transcription regulators by inhibiting their __.
degradation
Hedgehog signaling triggers a switch from transcriptional __ to transcriptional __.
- repression
- activation
What can excessive hedgehog signaling in adult cells lead to?
Cancer
In which organism was the first hedgehog protein discovered?
Drosophila
When the __ is mutated in Drosophila, the larva is covered with __ processes (denticles), resembling a hedgehog.
- Hedgehog gene
- spiky
What are the names of the genes encoding hedgehog proteins in vertebrates? (3)
- Sonic
- Desert
- Indian hedgehog
Hedgehog proteins mediate signaling through a latent transcription regulator called __(__).
Cubitus interruptus (Ci)
Cubitus interruptus (Ci) in the absence of hedgehog signal is __ and proteolytically cleaved in __.
- ubiquitylated
- proteasomes
Cubitus interruptus (Ci) is processed into __ that act as a transcriptional __, keeping hedgehog-responsive genes __, instead of __.
- smaller fragments
- repressor
- silent
- complete degredation
Which kinases are involved in the processing of the cubitus interruptus (Ci) protein? (3)
- PKA (protein kinase A)
- GSK1
- CK1
The function of the complex formed by __ and __ proteins keeps unprocessed cubitus interruptus (Ci) out of the nucleus.
- Fused
- Costal2
Hedgehog proteins __ the __ of cubitus interruptus (Ci), allowing it to function as a transcriptional __.
- block
- proteolytic processing
- activator
What are the names of the transmembrane proteins involved in hedgehog signaling? (3)
- Patched
- iHog
- Smoothened
In the absence of the hedgehog signal, __ keeps Smoothened sequestered and inactive.
Patched
The binding of hedgehog to __ and Patched inhibits the activity of Patched and induces __ and __.
- iHog
- endocytosis
- degradation
Upon hedgehog binding, __ translocates to the plasma membrane and this recruits a protein complex containing (3)
Smoothened
- Ci
- Fused
- Coastal2
When Costal2 is no longer able to bind the other three kinases, Ci is not cleaved and can now enter the __.
nucleus
Costal is no longer able to bind the other 3 kinase, __ no longer cleaved and can now enter the __ and activate the transcription of __
- Ci
- nucleus
- Hedgehog target genes
The increase in Patched proteins serves as a __ feedback mechanism to inhibit further hedgehog signaling.
negative
- This pathway involves latent transcription regulators that play a crucial role in stress, inflammatory, and innate immune responses.
- Overactivation of this pathway is often found in various human cancers.
NFκB-Dependent Signaling Pathway
has important functions during normal animal development; for example, in Drosophila, the Dorsal protein is essential for specifying the dorsal-ventral axis of the developing embryo.
NFκB signaling
NFκB signaling has important functions during normal animal development; for example, in Drosophila, the __ is essential for specifying the __of the developing __.
- Dorsal protein
- dorsal-ventral axis
- embryo
__ in Drosophila, __, in vertebrates, recognize pathogens and activate the NFκB pathway to trigger innate immune responses.
- Toll receptors
- Toll-like receptors
NFκB-Dependent Signaling Pathway is activated by __ and __
- tumor necrosis factor (TNF)
- interleukin-1 (IL-1)
NFκB-Dependent Signaling Pathway: Upon activation, __ and __ trigger a multiprotein ubiquitylation and phosphorylation cascade, leading to the release of __ from its inhibitory protein complex. Once released, it translocates to the __, where it activates the transcription of genes involved in inflammatory and innate immune responses.
- tumor necrosis factor (TNF)
- interleukin-1 (IL-1)
- NFκB
- nucleus
The NFκB family includes proteins such as (5)
- RelA
- RelB
- c-Rel
- NFκB1
- NFκB2.
an inhibitory protein that tightly binds to NFκB dimers, keeping them in an inactive state within the cytoplasm of unstimulated cells.
IκB
IκB is an inhibitory protein that tightly binds to __, keeping them in an __ state within the cytoplasm of unstimulated cells.
- NFκB dimers
- inactive
The specific IκB proteins include (3)
- κBα
- IκBβ
- IκBε
NFκB activates the gene that encodes __, leading to the synthesis of __ proteins.
- IκB
- IκB
Newly synthesized IκB proteins bind to NFκB, inactivating it and forming a __ feedback loop.
negative
__-induced responses create two types of NFκB activity, leading to different patterns of gene expression. What are the two type of this activity?
- TNFα
1. Short TNFα Exposure
2. Sustained TNFα Exposure
A brief exposure to TNFα produces a single, short pulse of NFκB activation, turning on __.
gene A
Prolonged TNFα exposure causes oscillations in NFκB activation, turning on __ (2).
- gene A
- gene B
hydrophobic signal molecules that diffuse directly across the plasma membrane and bind to intracellular receptors (transcription regulators)
Nuclear Receptor Superfamily
Nuclear receptor superfamily includes __, __, retinoids, and __, which diffuse directly across the plasma membrane to bind these receptors. Binding of these molecules to their respective intracellular receptor proteins __ the receptors’ ability to control the __ of specific genes.
- steroid hormones
- thyroid hormones
- vitamin D
- alters
- transcription
Nuclear receptors serve both as (2)
- intracellular receptors
- intracellular effectors
Receptors within the nuclear receptor superfamily whose ligands are not yet identified
Orphan Nuclear Receptors
- __ bind to specific DNA sequences adjacent to the genes that the ligand regulates.
- Ligand binding alters the conformation of the receptor protein, causing the inhibitory complex to __.
- The receptor binds __ proteins that stimulate __.
- Nuclear receptors
- dissociate
- coactivator
- gene transcription
- What possess an internal rhythm that dictates different behaviors at different times of the day?
- regulate cyclical changes in metabolic enzymes, such as those involved in the __ of humans.
- Circadian clocks
- sleep-wake cycles
- Internal oscillators that control diurnal rhythms.
- enable organisms to anticipate regular daily environmental changes and take appropriate actions in advance.
- function as timekeepers at the cellular level.
Circadian clocks
cells in the suprachiasmatic nucleus of the hypothalamus that control diurnal cycles of sleeping and waking, body temperature, and hormone release.
SCN cells
SCN cells receive cues from the __, which influence the __ and the rest of the body by releasing the hormone __.
- retina
- pineal gland
- melatonin
Circadian clocks have the ability to reset in response to __.
light
In __, circadian clocks are similar to those in humans and can be reset by externally imposed light and dark cycles.
Drosophila
- Circadian clocks generally depend on __ feedback loops.
- Oscillations in the activity of an intracellular signaling protein occur if that protein __ its activity with a long delay.
- The accumulation of certain gene products switches __ the transcription of their own genes.
- negative
- inhibits
- off
- In the circadian clocks, these proteins rise gradually during the day.
- they form a heterodimer, dissociate, and are transported into the nucleus.
- Tim (timeless) protein
- Per (period) protein
represses the transcription of Tim and Per genes
Per
