NFkB transcription factors, cell death, inflammation&cancer - week 9 Flashcards
(27 cards)
what is inflammation and why is it important
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.
what signs indicate inflammation
Some important signs that are indicative of inflammation are:
- Redness
- Heat
- Swelling
- Pain
how does the inflammatory response take place when a pathogen invades
- When a pathogen enters the skin of an individual, there are macrophages and mast cells that are able to fight against these pathogens.
- How they fight the pathogen is they produce cytokines or mediator of growth.
- 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.
- 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.
- 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.
what are the 2 types of inflammation
- Acute inflammation
- Chronic inflammation
what is acute inflammation
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.
what is chronic inflammation
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.
what human diseases can chronic inflammation lead to
Chronic inflammation can lead to other human diseases, such as:
- Atherosclerosis
- Asthma
- Multiple sclerosis
- Rheumatoid arthritis
- Inflammatory arthritis
- Inflammatory bowel disease
- Obesity
- Cancer
what is the link between inflammation and cancer
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
The connection between inflammation in cancer depends on which 2 pathways
The connection between inflammation and cancer can be viewed as consisting of 2 pathways, which are an:
- Extrinsic pathway
- Intrinsic pathway
what is extrinsic pathway and how does it lead to tumors
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.
what is intrinsic pathway and how does it lead to tumors
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.
what is transcription
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.
what are the 2 groups of transcription factors
There are 2 groups of transcription factors:
1. Basal transcription factors
2. Regulatory transcription factor
what are transcription factors
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.
what are the main components is the transcription factors made up of
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.
what is an inducible transcription factor
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.
how was NF-kB discovered
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
which family is NF-kB from
NF-kB is a protein family which consists of 5 members, which are:
* RelA/p65
* RelB
* c-REL
* p52
* p50
what is the Rel-homology domain and where is it located
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.
what is a dimer and what are the different dimeric combinations
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.
what is IKBa and what is its function
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.
what family is IKBa from and which domain of IKBa is important for NF-kB inhibition
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.
what does IKK do and what are the different IKK protein members
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.
what happens when IKK proteins are activated
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.
