NF-kB signalling: cell death, inflammation and cancer - II - week 10

Question 1

what are the 2 forms of programmed cell death

Answer 1

There are 2 forms of PCD:
1. Apoptosis
2. Necrosis/ Necroptosis

Apoptosis is programmed cell death thus intentional whereas necrosis is accidental as is caused by tissue injury and doesn’t require energy.
Necrosis and apoptosis are both controlled by specific genes.

Question 2

which form of PCD causes inflammation

Answer 2

In necrosis, the release of cellular content stimulate an inflammatory response while apoptotic cells do not stimulate an inflammatory response.
In necrosis, the release of cellular content stimulate an inflammatory response while apoptotic cells do not stimulate an inflammatory response.

Question 3

what is the differences between necrosis and apoptosis

Answer 3

Apoptosis:
- energy-dependent process
- suppression of inflammation
- plasma membrane intergrity maintained
- order DNA fragmentation
- cell first shrink, the nuclei condenses which forms apoptotic bodies. the apoptotic bodies are then eliminated by the immune system.

Necrosis/ necroptosis
- energy-independent process
- induction of inflammation
- plasma membrane integrity lost
- random DNA fragmentation
- cell swells and ruptures during demise which causes it to release cellular content

Question 4

why is NF-kB required role

Answer 4

The pro-survival activity of NF-kB plays crucial role in several biological or physiological processes within the immune system.
-NF-kB is able to block both forms of PCD.
-The activation of NF-kB is important downstream for several receptors found on the surface of cells of the immune system. These cell receptors include TNF-R, TRAIL and FAS.
-Also NF-kB is required for the activation of T and B lymphocytes.
-NF-kB is also important for the formation for the maturation of B cells that is required for the production of antibody.
- In contrast, the activity of NF-kB plays crucial role also outside of the immune system, for example it is important for the formation of the bone and for the development of the liver.

Question 5

what human diseases can be caused by NF-kB dyregulation

Answer 5

When NF-kB is dysregulated, the ability of NF-kB to control cell survival is imbalanced which can contribute to many human diseases, for example:
* Chronically inflammatory disease
* Inflammatory bowel disease
* Rheumatoid arthritis
* Metabolic and vascular disorder
* Cancer, development of a specific cancer
* Resistance of cancer cells to cancer therapy

Question 6

what is the main hallmark of cancer

Answer 6

Although there are more than 200 types of cancers, all cancer shares 6 hallmarks. One of the most common hallmarks is uncontrolled cell proliferation.

Question 7

what happen in normal tissue and in damaged cell

Answer 7

In normal tissues, the rate of cell proliferation, cell growth and cell death are kept in balance. This means during normal cell division when a cell is damaged it can either be repaired or cell death of the damaged cell can occur.
But if the damaged cell is not repaired and doesn’t undergo programmed cell death then its accumulates and continue to proliferate for several generations and this forms a mass of the tumor.

Question 8

what happens in normal growth control of skin

Answer 8

Normal growth control of skin
The skin consists of different layers and cells in the basal layer of the normal skin divide and one cell remains in the basal layer and one cell migrates to the surface layer of the skin. So essentially, we can say that each time one of the basal cells in the basal layer divide it produces 2 cells. One remains in the basal site and thus it is able to divide again, and the other migrates out of the basal layer to the surface and thus loses its ability to divide because it undergoes apoptosis and is then released from the surface. Thus, the number of dividing cells in the basal layer stays the same.

Question 9

what happens during the development of skin cancer

Answer 9

If programmed cell death/ apoptotic signals don’t work properly and thus cell death doesn’t occur then gradually the increased number of dividing cells create a growing mass which is called tumor. As more and more of these dividing cells don’t die and accumulate over the tissue then the tissue becomes disrupt. With each division both two newly formed cells will retain the capacity to divide leading to an increased number of dividing cells. This creates a growing mass called tumor
Therefore, the loss of ability of cells to undergo apoptosis or necrosis can be the cause of cancer development.

Question 10

which aspects is NF-kB transcription factors involved in, of cancer development and oncogenesis

Answer 10

NF-kB transcription factor is involved in several aspects of cancer development and oncogenesis. These aspects are:
- Cell Proliferation
- Invasion
- Metastasis
- Oncoproteins
- Differentiation
- Programmed cell death

Question 11

how is NF-kB linked to cancer development

Answer 11

Direct evidence from in-vivo and in-vitro models indicate that it is the ability of NF-kB to block programmed cell death is crucial for cancer development.

Question 12

what is TNFa and how was it discovered

Answer 12

TNFa is a cytokine that play a key role in immunity inflammation.
The protective function of NF-kB was first discovered in the context of cell response of TNF-alpha.

Question 13

how does TNFa cause cell death most of the time

Answer 13

The engagement of TNF-R with TNFa, initiates an intracellular death signalling that involves mitochondria. When cells are treated with TNFa, we expect that cells die because the engagement of TNFa to the TNF-R induce a death pathway which involves the mitochondria and the activation of caspases.

Question 14

why doesn’t TNF always result in cell death

Answer 14

But normally, despite the ability of TNF to kill cells, the stimulation of cells with TNFa doesn’t always result in cell death. This is because downstream of TNF-R there is the activation of NF-kB. NF-kB starts (induces) the transcription of pro-survival genes that block the activity of another protein called JNK. JNK usually induces the death pathway through the mitochondria. (JNK stands for c-Jun N-terminal Kinase).

Question 15

what is a kinase

Answer 15

Kinase is a specific protein that is able to transfer a phosphor (P) group from ATP to a target protein, the substrate, and the phosphorylated protein is able to do the function.
Most kinases act on both serine and threonine, others act on tyrosine.

Question 16

why is phosphorylation and de-phosphorylation important, with an example

Answer 16

phosphorylation and de-phosphorylation of protein is an important regulatory mechanism in cell division and in the cell cycle.
For example, JNK is a kinase that can phosphorylate a target protein, thus we can say that JNK through its kinase activity is able to affect the function of many proteins involved in cell division.

Question 17

what is phosphatase

Answer 17

phosphatase is an enzyme that removes a phosphate group from its substrate.

Question 18

which experiment indicates that RelA (which is a member of NF-kB family) is important for cell survival

Answer 18

the experiment which compares cells from RelA knockout mice and WT cells.
In the experiment, what was done was cells used from RelA knockout mice (cells from RelA knockout mice are cells that don’t have NF-kB because RelA is the primary component of NF-kB complex) and WT cells where treated with TNFa, at different hours. The results show that RelA knockout cells compared to WT cells die in response to TNFa. Thus, this experiment indicates that RelA (NF-kB) is important for the cell survival signalling downstream of TNF receptor because when it is not present the cells die.