NF-kB signalling: cell death, inflammation and cancer - II

What activates the classical NF-κB pathway?

Microbial products, mitogens, cytokines and stress

What do IKKs do in the NF-κB pathway?

Phosphorylation of IκB

What happens after phosphorylation of IκB?

Ubiquitination and proteolysis of IκB

What happens after IκB is degraded?

Activation of NF-κB

Where does NF-κB go after activation?

Translocates into the nucleus

What does NF-κB do in the nucleus?

Binds NF-κB target genes and induces gene activation

What processes are activated by NF-κB target genes?

Inflammation, immunity, development, cell survival

What is the pro-survival activity of NF-κB?

NF-κB blocks Programmed Cell Death (PCD)

What is Programmed Cell Death (PCD)?

Removal of unnecessary or damaged cells via an intrinsic suicide program

What are the two forms of Programmed Cell Death?

Apoptosis and necroptosis

What characterises apoptosis?

Energy-dependent process, suppression of inflammation, plasma membrane integrity, order DNA fragmentation, cell shrink, nuclei condense, formation of apoptotic bodies

What characterises necroptosis?

Energy-independent process, induction of inflammation, plasma membrane rupture, random DNA fragmentation, cell swell, ruptures during death, releasing of cellular contents

What are the biological roles of the pro-survival activity of NF-κB?

Cellular responses to the triggering of TNF-Rs, TLRs and Fas
B lymphopoiesis
Bone morphogenesis
B- and T-cell costimulation (CD40, CD28, etc.)
Liver development

What happens when NF-κB pro-survival activity is deregulated?

Leads to disease

What diseases are associated with NF-κB deregulation?

Cancer, chronic inflammatory disease (RA, inflammatory bowel disease), metabolic & vascular disorders (atherosclerosis)

What is cancer characterised by?

What is cancer characterised by?

What percentage of human cancers are related to exposure to carcinogens?

About 90%

What are carcinogens?

Agents that increase the likelihood of developing cancer

What do most carcinogens do?

Are mutagens that promote genetic changes in somatic cells

What do DNA alterations affect?

Gene expression that ultimately affect cell division or programmed cell death

How does cancer develop?

It is a multistep process

Do cancers originate from a single cell?

Yes

What is required for cancer development?

Multiple genetic changes to the same cell

What happens to cells during cancer development?

Cells and their offspring undergo a series of mutations, so cells grow abnormally

What happens in normal cells?

Cell damage → repair or apoptosis

What happens in cancer cells?

Mutations accumulate → uncontrolled growth

What does NF-κB act as in cancer?

Oncoprotein

What processes does NF-κB influence in cancer?

Differentiation, proliferation, metastasis, invasion, programmed cell death

What are NF-κB?

Transcription factors that block Programmed Cell Death (PCD)

What are the two forms of PCD?

Apoptotic and necroptotic

What happens when NF-κB regulation of PCD is deregulated?

Leads to a variety of human disease

What can TNF-R1 signalling activate?

Death pathway and survival pathway

What activates caspases?

Death pathway

What does NF-κB activation lead to?

Survival pathway and gene expression

What is a protein kinase?

An enzyme that modifies other proteins by phosphorylation

What is the MAPK cascade?

A signalling cascade involving MAP3K, MAP2K, and MAPK

What does the MAPK cascade regulate?

Cell division, differentiation, stress response

What does NF-κB inhibit?

TNFα-induced apoptosis

What does NF-κB inhibit in signalling?

TNFα-induced JNK activation

Is NF-kB an enzyme?

No

How does NF-κB typically influence apoptosis?

It generally suppresses apoptosis by inducing anti-apoptotic genes

If you inject siRNA that recognizes RelA within cells and treat them with TNFα they will not undergo apoptosis

False

How is it possible for a single gene to encode more than one polypeptide?

Introns can be removed from pre-mRNA in different combinations