NFkB transcription factors, cell death, inflammation&cancer - week 9

Question 1

what is inflammation and why is it important

Answer 1

Inflammation is the biological response to any infection, tissue injury or irritants. Inflammation is a short-term response to any injury, infection or irritant
It is a biological response thus it is controlled, and its an advantage for an organism.
A controlled inflammatory response is beneficial (provides protection against infection), but it can be detrimental if de-regulated (causes septic shock).
In 1908 the Nobel prize in medicine was awarded to Metchnikoff and Ehrlich.

Question 2

what signs indicate inflammation

Answer 2

Some important signs that are indicative of inflammation are:
- Redness
- Heat
- Swelling
- Pain

Question 3

how does the inflammatory response take place when a pathogen invades

Answer 3

1. When a pathogen enters the skin of an individual, there are macrophages and mast cells that are able to fight against these pathogens.
2. How they fight the pathogen is they produce cytokines or mediator of growth.
3. These mediator of growth and cytokines in turn activate an important process of the inflammatory response which is the extravasation. This extravasation allow other inflammatory cells to help the macrophages in the fight against the pathogen.
4. All the effectors involved in the inflammatory response are not able to discriminate between the pathogen and the host target thus after an inflammatory response there is some damage of the tissue.
5. When the pathogen is eliminated, these damages are then repaired, so after the elimination of an infectious agent there is a repair phase that repairs the damages caused by the inflammatory response.

Question 4

what are the 2 types of inflammation

Answer 4

1. Acute inflammation
2. Chronic inflammation

Question 5

what is acute inflammation

Answer 5

Acute inflammation usually last days or a couple of weeks, then the pathogen is eliminated and the elimination of the pathogen is followed by the repair phase.
short term response to injury, infections and irritation that usually results in healing. leukocytes infiltrate the damaged region, removing the stimulus and repairing the tissue.

Question 6

what is chronic inflammation

Answer 6

It occurs when acute inflammation fails to arrest infection.
Chronic inflammation is a longer-term response of an individual to a pathogen. Usually, the chronic inflammation last months to even years.
It is also long term response to other factors including viral infections stress, poor nutrition and processes related to aging. Prolonged chronic inflammation generates a series of destructive reactions that damage cells and lead to disease.
Repeated inflammatory process of chronic inflammation unleash a host defensive response including leukocytes proliferation, angiogenesis, oxidative reaction that ultimately alter the normal function of the cells.

Question 7

what human diseases can chronic inflammation lead to

Answer 7

Chronic inflammation can lead to other human diseases, such as:
- Atherosclerosis
- Asthma
- Multiple sclerosis
- Rheumatoid arthritis
- Inflammatory arthritis
- Inflammatory bowel disease
- Obesity
- Cancer

Question 8

what is the link between inflammation and cancer

Answer 8

This idea was made based on the fact that inflammatory cells were present in sample from tumours.
Then other molecular and genetic studies have shown and confirm that inflammation is linked to cancer.
First observations: inflammatory cells were present in biopsied samples from tumors and tumors often arose at sites of chronic inflammation

Question 9

The connection between inflammation in cancer depends on which 2 pathways

Answer 9

The connection between inflammation and cancer can be viewed as consisting of 2 pathways, which are an:
- Extrinsic pathway
- Intrinsic pathway

Question 10

what is extrinsic pathway and how does it lead to tumors

Answer 10

The extrinsic pathway is activated by inflammation or infection from a pathogen. Also the extrinsic pathway activates transcription factors including NF-kB.
The connection between inflammation and cancer depends on activation of specific transcription factors like NF-kB, STAT3 or HIF1, these transcription factors induce, activate and produce an inflammatory micro-environment which over time leads to inflammatory tumor micro-environment.

Question 11

what is intrinsic pathway and how does it lead to tumors

Answer 11

The intrinsic pathway is activated by genetic events that can cause cancer. Genetic events include mutations of an oncogene or a chromosome amplification that leads to the activation of particular transcription factors including NF-kB
So essentially, transformed cells that have genetic mutation induces the activation of transcription factors that in turn produce inflammatory mediators which activates inflammatory cells and produce an inflammatory micro-environment which leads to inflammatory tumor micro-environment.

Question 12

what is transcription

Answer 12

Transcription Translation
DNA ————-> RNA ———–> protein

Transcription occurs in the nucleus and involves the function of DNA polymerases.
RNA polymerases enzyme is not able to work alone and needs help from transcription factors.

Question 13

what are the 2 groups of transcription factors

Answer 13

There are 2 groups of transcription factors:
1. Basal transcription factors
2. Regulatory transcription factor

Question 14

what are transcription factors

Answer 14

Transcription factors are proteins that are involved in the regulation of gene expression, that binds to specific regions within the gene and are able to activate or inhibit the rate of transcription.

Question 15

what are the main components is the transcription factors made up of

Answer 15

The structure of the transcription factor is important for the function.
-they have a DNA binding domain called DBD. This domain consists of amino acids that can recognise specific sequence on the DNA.
-At the structural level, the transcription factors contains also a trans-activating domain – TAD, which contains binding sites for other proteins such as co-regulators that is important for the interaction with RNA polymerases.
- some transcription factors have also another important domain, but it optional (meaning not all transcription factors contain this) called SSD, signal sensing domain, this domain is a ligand-binding domain, so the activation of these transcription factors depends on external signals that are able to directly bind the transcription factor.

Question 16

what is an inducible transcription factor

Answer 16

There are different types of transcription factors, some of them are inducible factors, this means that signals from the environment (signals from other cells) activate inducible transcription factors which bind to regulatory region within a gene and increase or decrease the level of the transcription.
One of the most studied inducible transcription factor is called NF-kB, which stands for Nuclear transcriptional factor.

Question 17

how was NF-kB discovered

Answer 17

The discovery and the identification of NF-kB dates back to 1986, when it was identified in the nuclei of mature B cells.
B cells are cells that produce antibodies. NF-kB was discovered as a protein that control the expression of the light chain of the antibody.The discovery was made by David Baltimore and published in CELL in 1986. After its discovery, it was shown that NF-kB is not only present in B cells but it is present in every cell of our body.

There are now over 40,000 articles on the subject of NF-kB

Question 18

which family is NF-kB from

Answer 18

NF-kB is a protein family which consists of 5 members, which are:
* RelA/p65
* RelB
* c-REL
* p52
* p50

Question 19

what is the Rel-homology domain and where is it located

Answer 19

All 5 proteins members in NF-kB family share an important domain which is the Rel- homology domain. All the members contain this domain implies that this domain is important for the function of the NF-kB transcription factors.
This REL homology Domain is located at the N-terminus of the protein and its function is important for the binding of the transcription factor to the DNA.

Question 20

what is a dimer and what are the different dimeric combinations

Answer 20

NF-kB refers to a dimer and all 5 members can form homo-dimers or hetero-dimers. So, this means that different combination of all members contribute to the regulation of a distinct set of gene. The term NF-kB refers to a family of inducible dimeric transcription factors that recognize a common sequence motif, the “kB site”

The possible dimeric combinations are:
- p50:p50
- p50:p65
- p50:RelB
- p65:p65
- RelB:RelB
- p52:RelB
The most common complex is p50:p65 which is the classical NF-kB heterodimer that is present in most cells of our body.

Question 21

what is IKBa and what is its function

Answer 21

In most cells NF-kB is present in the cytosol, and it is in the form of inactive proteins. This is because the dimer is bound to another protein that is called IkBa, which retains the dimers in the cytosol and thus inhibits NF-Kb pathway.
When there is no lkBa, the dimer of NF-kB is active and it enters into the nucleus where transcription starts of target genes. Thus Transcription occurs when IKBa ( which is the inhibitor protein of the NF-kB dimer)is not present in the cytosol.

Question 22

what family is IKBa from and which domain of IKBa is important for NF-kB inhibition

Answer 22

IKBa is also a family of protein that consists of 5 members, which are:
- alpha
- beta
- epsilon
- gamma
- Bcl3

All of IKBa family members share Ankyrin repeat domains, which are important for the binding of IKBa to the dimer of NF-kB and therefore it is important for the inhibition of NF-kB.

Question 23

what does IKK do and what are the different IKK protein members

Answer 23

When IkB is not present in the cytosol, NF-kB enters the nucleus. The activation of NF-kB is associated with a phosphorylation event of lKBa. The phosphorylation of lKBa is caused by IKK protein members, which are:
IKKa, IKKb and IKKgamma protein.

Question 24

what happens when IKK proteins are activated

Answer 24

Different signals from outside of the cells, which can be cytokines, mitogens, bacteria all induce the activation of IKK proteins. Which in turn induce the phosphorylation of IKBa. This phosphorylation cause the ubiquitination and degradation of IKBa. And so the NF-kB dimers can enter the nucleus where it binds to a specific DNA sequence and induce the transcription of specific genes involved in inflammation, immunity, development or cell survival.

Question 25

what is the function of NF-kB

Answer 25

NF-kB blocks programmed cell death known as PCD. So essentially NF-kB can block PCD and in doing so is able to promote survival of cells. Also NF-kB induce the expression of a set of genes involved in different cellular activities, including cell survival.

Question 26

what is programmed cell death

Answer 26

Programmed cell death is an important biological process throughout the life of any organism. Essentially programmed cell deaths helps the body to get rid of unwanted cells that the body doesn’t need. These cells can either be infected cells, transformed cells or damaged cells.

Question 27

why is programmed cell death important

Answer 27

PCD is the kind of suicide programme as it is regulated by a defined genetic programme, thus this types of cell death is controlled by specific genes. Programmed cell death is important because an organism can eliminate dangerous cells using it.
it is an important mechanism in both development and homeostasis in adult tissue for removal of either superfluous, infected, transformed, or damaged cells.
PCD also plays an important role also in the development of the embryo and in the maintenance of homeostasis of tissue.