NF-κB & p53 signalling pathways Flashcards
lecture 17
What are the main functions of NF-kB in cellular response?
NF-kB regulates gene expression involved in repair, programmed cell death, and immune response to environmental challenges like DNA damage, infection, and hypoxia.
What is the Rel Homology Domain (RHD) in NF-kB?
The RHD encodes the DNA-binding and dimerisation functions of NF-kB.
How are p50 and p52 proteins of NF-kB produced?
They are proteolytically processed from precursor proteins p105 and p100, respectively.
What role do ankyrin repeats in p100 and p105 play?
They function as IκB inhibitors by keeping NF-kB inactive in the cytoplasm.
What are the key environmental and cellular stressors that activate NF-kB?
DNA damage, infection, hypoxia, physical stress, carcinogens, tumour promoters, and oncogene activation.
Why is NF-kB often aberrantly activated in cancer?
Due to factors like genetic alterations (e.g., IκB deletion), cytokines (e.g., IL-1, TNF), and tumour promoters (e.g., UV, PMA).
What tumour-promoting functions are associated with aberrant NF-kB activity?
Proliferation: Cyclin D1, c-Myc.
Survival: Bcl-xL, XIAP.
Angiogenesis: VEGF, IL-8.
Metastasis: ICAM-1, VCAM-1.
Why might directly targeting NF-kB be challenging in cancer therapy?
NF-kB also plays crucial roles in immune response, apoptosis, and epithelial homeostasis, so its inhibition can have adverse effects.
What are some key components of p53 structure and their functions?
N-terminal domain: Contains transactivation and proline-rich domains, regulating apoptosis.
Core domain: Binds specific DNA sequences.
C-terminal domain: Contains a tetramerisation domain and regulatory DNA binding site.
What cellular processes does p53 regulate?
Cell cycle arrest (via p21), apoptosis (via Bax, PUMA), survival (via Bcl-xL), and DNA repair.
How are NF-kB and p53 activated by similar stimuli?
Both are activated by DNA damage, stress, and oncogene activation, requiring mechanisms to integrate their activities.
How does the balance between NF-kB and p53 influence cellular response?
It determines whether cells undergo repair, survival, or apoptosis in response to DNA damage.
What is the role of mutant p53 in cancer?
Mutant p53 loses tumour suppressor functions and can contribute to aberrant NF-kB activity, promoting tumour progression.
How does NF-kB contribute to rheumatoid arthritis (RA) via immune cells?
By activating immune cells, NF-kB drives inflammation through cytokine production (e.g., IL-1, IL-6, TNF) and promotes tissue damage.
What are the four ways NF-kB activation in fibroblast-like synoviocytes (FLS) contributes to RA?
Stimulating pannus formation.
Promoting cell proliferation (via Cyclin D1).
Enhancing cytokine production (e.g., IL-1, IL-6).
Increasing RANKL expression for bone resorption.
