Flashcards in Biochemistry - Cell Cycle Disregulation Deck (15):
How does Rb regulate cell cycle?
It prevents activation of E2F transcription factor
Cdk2 cyclin A inactivates Rb so that EF2 can be released
What INTERcellular signal promotes cell division?
Mitogens (growth factors)
Some mitogens activate receptor tyrosine kinase. This initiates a signal transduction pathway tha leads to the expression of G1 cyclin D genes.
In terms of intercellular signals, what are cell cycle negative controls?
Protein ligans known to inhibit cell division when growth is not necessary
When is TGF-beta secreted and what does it do?
TGF-beta is a ligand that is released under growth-inhibitory conditions.
When TGF-beta binds to it's receptor, it initiates a signaling cascade which blocks phosphorylation of Rb. This means that Rb remains bound to E2F, keeping E2F inactive. This switches off the cell cycle.
How can a cell initiate apoptosis in a neighbouring cell?
A membrane bound protein called FasL protrudes from the cell surface.
Its presence is a signal to the adjacent cell to self-destruct.
FasL binds to 3 Fas receptors (a trimer) on the neighboring cell. Trimerisation of cytoplasmic domains activated a molecule called Apaf, which activated an initiator caspase. This leads to cell death.
What do cancer promoting mutations do?
a. Increase ability of cell to proliferate;
b. Decrease susceptibility of cell to apoptosis;
c. Increase general mutation rate in cell or its longevity
What causes cancer?
An accumulation of mutations that leads to uncontrolled proliferation.
What are the two general kinds of mutations associated with tumors?
1. Oncogene mutations
- gain of function
- mutation only required in one allele
- gene in its normal unmutated form = proto-oncogene
- proto-oncogenes normally produce factors that stimulate cell division. They regulate notmal cell proliferation or apoptosis.
- Oncogene active even in absence of signal, leading to an increased rate of proliferation or prevention of apoptosis.
2. Tumor suppressor gene mutations
- loss of function
- both alleles must be mutated and have no activity
- tumor suppressor genes usually produce factors that inhibito cell division i.e. arrest cell cycle or induce apoptosis. If mutated, cells lose ‘brake’ that can stop cell proliferation.
- i.e. p53
What is the consequence of being heterozygous for a tumor-suppressor gene?
These people are predisposed to cancer.
These people are predisposed to cancer.
The cell has a much longer lifetime. More chance of accumulating proliferating-promoting mutations. When these mutations take place, the cell would usually induce apoptosis but in this case it can’t.
What are some of the types of mutations that could cause an oncogene?
- point mutations that alter structure/function
- deletions that result in loss of protein domains
- gene fusions, often resulting from translocations
- sometimes mutations result in mis-expression, with proteins expressed in the wrong place or time
What is an example of an oncogene caused by gene fusion?
Brc1-abl fusion onco-protein - Chronic myelogenous leukaemia.
Structurally altered oncoprotein caused by gene fusion. The abnormality is termed ‘Philadelphia chromosome’ or ‘Philadelphia translocation’ and is caused by a translocation between Chromosome 9 and 22.
Result: onco-protein causes permanent protein kinase activity. Chronic myelogenous leukaemia.
What is an example of a tumor-suppressor gene mutation?
Normal p53 is a transcription factor that is activated in response to DNA damage. It prevents cell cycle progression to allow repair and causes severely damaged cells to undergo apoptosis.
The mutated form eliminates apoptotic response, allowing damaged cells to survive and therefore elevating mutation level.
~50% of all tumors have mutated p53
What are some of the viruses associated with cancer?
- mutates and rearranges proto-oncogenes
- inserts strong promoters near proto-oncogenes
- causes cervical cancer by inactivating Rb and p53
- Burkitts lymphoma
- T cell leukaemia