Cell Death And Cancer Flashcards
What is the role of p53 ?
The p53 protein is the guardian of the genome and it plays a central role in the checkpoint pathways of the cell cycle
Summarise DNA damage
- DNA damage arises as a result of normal cellular processes
- single and double stranded breaks in DNA trigger activation of the ATM protein kinase enzyme
- double stranded breaks are caused by environmental exposure
- single stranded breaks in DNA are the most common with ~ 10000 per day as a result of spontaneous DNA decay
What is the response to double stranded DNA breaks ?
- ATM phosphorylates checkpoint kinases which phosphorylate p53
- phosphorylated p53 is unable to bind Mdm2
- phosphorylated p53 is protected from degradation and this activates 2 events : cell cycle arrest and cell death
- phosphorylated p53 activates the gene coding for p21 that halts progression of the cell cycle by inhibiting activity of different Cdk-cyclins
What is the key protein in the cell death pathway ?
Puma (p53 upregulated modulator of apoptosis) is the key protein which inhibits Bcl-2 (an apoptosis inhibitor) and so cell death can occur
What is the role of Ras proteins ?
- the Ras pathway synthesises cyclins and Cdks
- Ras proteins play an essential role in transduction of signals from cell surface receptors to the nucleus
Summarise the Pl 3-Kinase-Akt pathway
- activated by stimulatory growth factors
- leads to cell death (apoptosis) or cell survival and proliferation (growth)
- ultimately leads to Akt phosphorylation
Which 2 pathways does Akt mediate ?
- cell death (apoptosis)
- cell growth
How are damaged and diseased cells eliminated ?
By apoptosis and necrosis
What is apoptosis ?
- programmed cell death in which singular cells are killed
- involves dismantling the nucleus and the cell contents with no inflammation
What is necrosis ?
- a type of cell death involving more than 100 cells
- it involves swelling and rupture of injured swells
Describe the steps of apoptosis
1) as cell begins apoptosis the cell shrinks and the chromatin condenses
2) fragmentation of the nucleus occurs and individual parts of the cell are fragmented so there is no inflammation
3) apoptic bodies form so they can be engulfed by phagocytosis
What is the role of caspases ?
Caspases are the proteins that control apoptosis
What are the 2 main routes of apoptosis ?
- intrinsic route
- extrinsic route
Describe the extrinsic route of apoptosis
1) a death receptor is embedded in the host cell and a cytotoxic T lymphocyte binds to it
2) the initiator procaspase matures into an initiator caspase and the executioner procaspase matures into an executioner caspase
3) apoptosis is activated
Give an example of a pro apoptotic protein
Bad : Bcl-2-associated death promoter
Describe the intrinsic route of apoptosis
1) initiated by signals from within the cell
2) regulated by maintaining a balance between 2 proteins found in the mitochondrial membrane
3) mitochondrial substances such as cytochrome c and calcium leak out into the cytoplasm
4) caspase-9 is assembled into a complex known as an apoptosome
What is cancer ?
A disease that arises from abnormalities of cell function
- there are ~ 200 types in humans
What percentage of all cancers are derived from a mutation of p53 ?
75%
What is cell differentiation ?
A process of cells acquiring specialised properties
Summarise the differences between normal growth of cells and tumour growth
- in normal growth each cell division gives rise to 1 cell which has the capacity to divide and 1 cell which has the capacity to differentiate and so there is no net accumulation of dividing cells
- in tumour growth each cell division is not balanced with death or differentiation and so there is a net increase in the number of cells dividing
What are the 2 types of tumours ?
1) benign - grow in a confined local area and are rarely dangerous
2) malignant - invade surrounding tissues and spread to parts of the body
Give some characteristics of benign tumours
- cells tend not to spread
- most grow slowly
- do not invade nearby tissue
- do not metastasise
Give some characteristics of malignant tumours
- cells can spread
- usually grow fairly rapidly
- often invade nearby tissues
- may recur after removal
How are cancer cells immortalised ?
Most cancer cells produce telomerase - an enzyme that adds telomere sequences to the ends of DNA molecules causing immortality of cancer cells
What is the multi step process through which cancer arises ?
1) initiation - normal cells are converted into a pre cancerous state and sensitised to further change
2) promotion - sensitised cells are repeatedly exposed to cancer promoting agents
3) tumour progression - once a tumour is formed it will grow and differentiate
What is angiogenesis ?
It is the development of new blood vessels
- required for tumours to grow beyond a few millimetres in diameter
What is invasion ?
Direct migration and penetration of cancer cells into neighbouring tissues
What is metastasis ?
The ability of cancer cells to enter the bloodstream and travel to distant sites
Describe the process of metastasis
1) cancer cells invade surrounding tissues and vessels
2) cells are transported by the circulation system
3) cells re invade and grow at new locations
Give 6 hallmarks of cancer
1) self sufficiency in growth signals
2) insensitivity to antigrowth signals
3) evasion of apoptosis
4) limitless replication potential
5) sustained angiogenesis
6) tissue invasion and metastasis
Describe the process of necrosis
1) reversible swelling of the cell
2) eventually will get irreversible swelling of the cell
3) disintegration of the cell
