Ch6.12

Question 1

What event initiates the activation of NF-κB from its inactive state in the cytoplasm?

Answer 1

Phosphorylation and subsequent degradation of IκB releases NF-κB, allowing it to migrate to the nucleus.

Question 2

How does phosphorylation of IκB affect NF-κB signaling?

Answer 2

Phosphorylation tags IκB for degradation, liberating NF-κB to translocate into the nucleus and activate gene expression.

Question 3

What is the role of IKK in the NF-κB signaling pathway, and how is it activated?

Answer 3

IKK phosphorylates IκB, leading to its degradation. It is activated by various signals like TNF-α, IL-1β, ROS, and anti-cancer drugs.

Question 4

Name two specific genes induced by NF-κB that promote cell survival in cancer.

Answer 4

Bcl-2 and IAP (inhibitors of apoptosis) genes.

Question 4

Why is NF-κB activation significant in the context of cancer progression?

Answer 4

NF-κB promotes cancer by inducing genes involved in cell proliferation and survival, including anti-apoptotic proteins like Bcl-2.

Question 5

In which type of cancer is the REL gene, encoding an NF-κB subunit, frequently amplified, and what is the consequence of this amplification?

Answer 5

Diffuse large B-cell lymphoma; REL amplification increases NF-κB activity, promoting cell survival and proliferation.

Question 5

Describe how the NF-κB signaling pathway is linked to both cell proliferation and survival in breast cancer.

Answer 5

NF-κB is constitutively active in breast cancers, inducing genes like myc and cyclin D1, promoting cell cycle progression and survival.

Question 6

How does the deregulation of NF-κB contribute to the pathogenesis of T- and B-cell lymphomas?

Answer 6

Amplification of REL or translocations affecting NFKB2 enhance NF-κB signaling, promoting unchecked proliferation and survival in lymphomas.

Question 7

Explain the role of NF-κB in preventing apoptosis and supporting cancer cell proliferation.

Answer 7

NF-κB induces anti-apoptotic genes (e.g., Bcl-2) and proliferative genes (e.g., myc), which support tumor growth and resistance to cell death.

Question 8

How does NF-κB contribute to oncogenesis despite rare mutations in its components in human cancers?

Answer 8

NF-κB is often constitutively activated by overexpression of upstream activators, such as IKKε in breast cancer, rather than direct mutations.

Question 9

Describe the proteolytic cleavages necessary for Notch receptor activation and their significance in signal transduction.

Answer 9

Upon ligand binding, Notch undergoes two proteolytic cleavages—one in the ectodomain and another in the transmembrane domain—releasing the intracellular fragment that migrates to the nucleus.

Question 10

What distinguishes the Notch signaling pathway from receptor tyrosine kinase pathways in terms of signal duration and amplification?

Answer 10

Notch signaling is proportional to ligand binding and occurs once per receptor, while tyrosine kinase receptors amplify signals repetitively after ligand binding.

Question 10

How do truncated forms of the Notch receptor contribute to oncogenesis?

Answer 10

Truncated Notch, which contains only the cytoplasmic domain, can act as a potent oncogene by continuously activating transcription in the absence of ligand.

Question 10

Explain the cellular context-dependent behavior of Notch signaling as both an oncogene and a tumor suppressor.

Answer 10

In hematopoietic malignancies, Notch acts as an oncogene, while in certain carcinomas, it functions as a tumor suppressor.

Question 10

What are the two ligands of the Notch receptor, and how are they implicated in cervical and prostate carcinomas?

Answer 10

Jagged and Delta; overexpression of these ligands is associated with increased Notch activity in these carcinomas, promoting tumor progression.

Question 10

How does the Notch pathway contribute to T-cell acute lymphocytic leukemia (T-ALL)?

Answer 10

Constitutively active forms of Notch due to deletions in NOTCH-1 are found in 60% of T-ALLs, driving uncontrolled cell growth.

Question 11

Describe how the ligand-binding event in Notch signaling leads to transcriptional activation in the nucleus.

Answer 11

Ligand binding triggers proteolytic cleavage of Notch, releasing the intracellular domain to migrate to the nucleus and activate transcription.

Question 12

How do constitutively active forms of Notch contribute to hematopoietic malignancies, and what genetic alterations are involved?

Answer 12

Deletions in the extracellular domain of NOTCH-1 lead to constitutive signaling, driving malignant transformation in hematopoietic cells.

Question 13

What role does increased expression of Notch ligands play in the progression of certain carcinomas?

Answer 13

Increased ligand expression enhances Notch signaling, promoting tumor cell survival, proliferation, and differentiation in cancers like cervical and prostate carcinomas.

Question 13

Why is the overexpression of nuclear localized Notch fragments a marker of active Notch signaling in tumor cells?

Answer 13

It indicates continuous signaling activation, as the intracellular Notch fragment functions in the nucleus to drive oncogenic transcription.

Question 14

Explain how mutations in the PTCH gene contribute to basal cell carcinoma development.

Answer 14

Mutations in PTCH prevent it from inhibiting Smoothened, leading to constitutive activation of Gli proteins and uncontrolled cell proliferation.

Question 14

What is the role of Gli proteins in the Hedgehog signaling pathway, and how do they regulate gene expression?

Answer 14

Gli proteins act as transcriptional regulators—Gli activators promote gene expression, while Gli repressors inhibit it, depending on Hedgehog signaling.

Question 15

Describe the mechanism by which Smoothened influences Gli activity following Hedgehog ligand binding.

Answer 15

Ligand binding to Patched releases inhibition on Smoothened, allowing it to activate Gli proteins, which then translocate to the nucleus to drive transcription.

Question 15

How does the Hedgehog pathway contribute to paracrine signaling in tumors of the gastrointestinal tract?

Answer 15

Hedgehog ligands produced by epithelial carcinoma cells activate Patched receptors in stromal cells, which in turn send mitogenic signals back to the carcinoma cells.

Question 15

What is the significance of Hedgehog pathway activation in stromal cells surrounding carcinomas, and how does it affect tumor growth?

Answer 15

Stromal cells activated by Hedgehog ligands secrete growth and survival signals that support carcinoma cell proliferation and tumor progression.

Question 16

How does the inactivation of the Patched receptor lead to constitutive activation of Smoothened in cancers?

Answer 16

Without Patched inhibition, Smoothened continuously activates Gli proteins, leading to uncontrolled gene expression and cancer progression.

Question 17

What is Gorlin syndrome, and how is it related to the Hedgehog signaling pathway?

Answer 17

Gorlin syndrome is caused by germ-line mutations in PTCH, leading to increased susceptibility to basal cell carcinomas and other tumors due to uncontrolled Hedgehog signaling.

Question 17

What are the implications of SUFU mutations in the development of medulloblastomas?

Answer 17

SUFU mutations impair its inhibitory function on Gli proteins, leading to unchecked activation of Hedgehog signaling and tumor development.

Question 18

How does the interaction between Gli proteins and Smoothened in the primary cilium regulate transcriptional outcomes?

Answer 18

Activation of Smoothened in the primary cilium prevents the cleavage of Gli proteins, allowing the full-length activator forms to drive transcription in the nucleus.

Question 18

What experimental evidence supports the role of Hedgehog signaling in small-cell lung carcinoma (SCLC) progression?

Answer 18

Elevated Hedgehog ligand levels and Gli activity in SCLC have been correlated with tumor proliferation, and anti-Hedgehog treatment has shown tumor growth inhibition.

Question 19

What role does the TGF-β pathway play in both tumor suppression and promotion during different stages of cancer?

Answer 19

In early cancer stages, TGF-β suppresses cell proliferation, while in later stages, it promotes tumor invasiveness and metastasis.

Question 20

How do Smad transcription factors bind DNA, and why is their binding considered weak on its own?

Answer 20

Smads bind a specific tetranucleotide sequence, but this interaction is weak without cooperative binding with other transcription factors.

Question 20

Explain how Smad proteins achieve cooperative DNA binding through interactions with other transcription factors.

Answer 20

Smads form partnerships with over 130 different transcription factors, enhancing their DNA binding and regulatory strength through protein-protein interactions.

Question 21

What is the impact of the loss of Smad proteins on epithelial cancer cell behavior, particularly in pancreatic carcinoma precursors?

Answer 21

Loss of Smads allows cells to escape TGF-β-mediated growth inhibition, promoting unchecked cell proliferation and tumorigenesis.

Question 22

What is the impact of the loss of Smad proteins on epithelial cancer cell behavior, particularly in pancreatic carcinoma precursors?

Answer 22

Loss of Smads allows cells to escape TGF-β-mediated growth inhibition, promoting unchecked cell proliferation and tumorigenesis.

Question 23

How does TGF-β signaling contribute to the invasive phenotype of advanced carcinomas?

Answer 23

TGF-β induces genes that promote epithelial-to-mesenchymal transition (EMT), enhancing tumor cell motility, invasiveness, and metastasis.

Question 24

Describe the mechanism by which activated Smads induce or repress gene expression.

Answer 24

Activated Smads bind to DNA and associate with co-transcription factors to either activate or repress the transcription of target genes.

Question 25

How does the presence of more than 130 transcription factor partners influence the function of Smad proteins in gene regulation?

Answer 25

The diversity of transcription factor partners allows Smads to regulate a wide range of genes in different contexts and tissues, influencing various cellular processes.

Question 26

What specific tetranucleotide sequence do Smad proteins recognize, and why is this binding insufficient for strong DNA association?

Answer 26

Smads recognize the sequence 5’-GTCT-3’, but their binding is weak without cooperative interactions with other transcription factors.

Question 27

What evidence suggests that TGF-β signaling shifts from a tumor-suppressive to a tumor-promoting role during cancer development?

Answer 27

In early stages, TGF-β inhibits proliferation, but in later stages, it promotes EMT, invasion, and metastasis, indicating a role in tumor progression.

Question 27

In what ways do cancer cells evade the growth-inhibitory effects of TGF-β signaling during tumor progression?

Answer 27

Cancer cells often lose functional Smad proteins or other components of the TGF-β pathway, allowing them to bypass TGF-β-mediated growth arrest.

Question 28

How do dual-address signaling pathways like Jak–STAT and Wnt–β-catenin operate at a mechanistic level?

Answer 28

Ligand binding activates signaling that releases transcription factors (e.g., STAT or β-catenin) from the cytoplasm, allowing them to translocate to the nucleus and regulate gene expression.

Question 28

What makes the Notch, Hedgehog, and TGF-β pathways distinct from other signaling pathways involved in cancer?

Answer 28

These pathways directly affect gene transcription through the release or activation of intracellular domains or Smads, leading to immediate transcriptional changes.

Question 29

How does the deregulation of dual-address signaling pathways contribute to neoplastic transformation?

Answer 29

Deregulated signaling results in uncontrolled gene transcription, driving proliferation, survival, and differentiation associated with cancer.

Question 30

Why are mutations in direct signaling components often unnecessary for the constitutive activation of pathways like NF-κB and Hedgehog in cancer?

Answer 30

Upstream activators or environmental signals often trigger these pathways, leading to chronic activation without the need for mutations in the pathway components themselves.

Question 31

Explain the significance of paracrine signaling in the Hedgehog pathway, particularly in the tumor microenvironment.

Answer 31

Tumor cells produce Hedgehog ligands, which activate signaling in nearby stromal cells, inducing them to secrete growth factors that support the tumor’s growth and survival.

Question 32

How do the deregulated pathways discussed (NF-κB, Notch, Hedgehog, TGF-β) contribute to cancer cell resistance to chemotherapy?

Answer 32

These pathways induce the expression of survival genes, anti-apoptotic factors, and efflux pumps, which enhance cancer cell resistance to chemotherapeutic agents.

Question 32

What is the role of reactive oxygen species (ROS) in activating NF-κB signaling, and how is this linked to cancer therapy resistance?

Answer 32

ROS can activate NF-κB by inducing IKK activity, leading to increased expression of anti-apoptotic genes and promoting therapy resistance in cancer cells.

Question 33

How do components of the dual-address signaling pathways interact with the cell cycle machinery to influence tumor growth?

Answer 33

Transcription factors released by these pathways (e.g., β-catenin, NF-κB, or Smads) induce cyclins and other cell cycle regulators that drive cancer cell proliferation.

Question 34

Why do different cancers show preferential activation of specific dual-address pathways, such as Hedgehog in basal cell carcinoma and NF-κB in lymphomas?

Answer 34

The specific pathways activated depend on the tissue type and the genetic alterations present in the cancer, leading to context-specific oncogenic signaling.

Question 35

How do cross-talk and feedback loops between these signaling pathways contribute to the complexity of cancer progression and therapeutic challenges?

Answer 35

Cross-talk between pathways (e.g., NF-κB and TGF-β) creates feedback loops that enhance resistance to treatment, tumor adaptability, and complicates therapeutic targeting.

Question 36

Cross-talk between pathways (e.g., NF-κB and TGF-β)

Answer 36

The interaction between these two pathways can occur at multiple levels. For instance, TGF-β can induce the expression of certain NF-κB target genes, thereby enhancing NF-κB activity. Conversely, NF-κB can influence TGF-β signaling by modulating the expression of TGF-β receptors or Smad proteins. This interplay can lead to a feedback loop where TGF-β enhances NF-κB signaling, promoting cell survival and proliferation, while NF-κB can suppress the growth-inhibitory effects of TGF-β, contributing to a more aggressive tumor phenotype.