Lecture 28 Flashcards
How do Polycyclic aromatic hydrocarbons act as carcinogens?
Cause damage to DNA resulting in the cell losing the ability of normal apoptosis and become neoplastic
What is the result of the loss of apoptotic mechanisms?
Cancer cells can survive in the wrong location and invade the adjacent tissue, this also can aid in the development of metastasis as it result in a loss of anoikis
It can also result in therapy resistant cells
What is the FAS ligand cell death pathway?
FasL binds to Fas, production of FADD, activator of initiator caspase, activator of effector caspase, substrate cleavage and cellular death
How can the Fas death pathway be impaired in cancers and what are the implications of this?
Signalling can be blocked via deletion of the death domain of the Fas receptor
This can result in cancer cells expressing FasL but not killing themselves, this can be beneficial to the tumour as FasL can kill tumour invading lymphocytes generating area of immune privilege
What is the evidence behind the counter attack theory where it is proposed that Fas resistant cells express FasL?
Cells in whihc FasL was suppressed:
Could not kill Fas+ lymphoid cells
Grew less efficiently as tumours
Generated tumours containing increased numbers of tumour infiltrating lymphocytes
How is BCL-2 expression deregulated?
B cell follicular lymphomas posses a t(14;18) where the BCL-2 translocated into the IgH locus
What are the consequences of a deregulated BCL-2 gene?
Small Lymphocytes persist for longer than there normal lifespan
This occurs as BCL-2 is an apoptotic regulator, which is antiapoptotic as it closes membrane pores in the mitochondria preventing apoptotic death
What are the apoptotic regulator proteins and how do they function?
Bcl-2 and Bcl-XL are antiapoptotic as they close membrane pores in the mitochondria
Bax is proapoptotic which opens membrane pores in the mitochondria
How does mutant EGFR regulate cell death?
This EGFR drives Bcl-Xl expression which acts as an antiapoptotic death
How do stomach and colon cancers typically change cell death regulation?
Often these cancers have mutated Bax genes resulting in a loss of apoptosis
What is the relationship between the Fas death pathway and the mitochondrial death pathway?
The pathway from Fas causes activation of an initiator caspase which cleaves BCL-2 resulting in loss of its antiapoptotic affect and therefore amplification of the Fas death pathway occurs via the mitochondrial death pathway
What are the two mechanisms through which p53 can be inactivated?
Mutation of the first allele, with a loss of chromatin containing the remaining functional allele
Cancers of connective tissue commonly have an amplified MDM2 gene, this protein binds, inactivates and destroys p53
What is Li-Fraumeni syndrome?
A condition where several cancer types appear in young people due to the inheritance of a mutant TP53 allele
What are the two mechanisms through which p53 regulates and prevents the development of cancer?
p53 responds to DNA damage causing the death of cells with harmful mutations loss of p53 function may make cells resitant to chemotherapy
p53 responds to unregulated proliferation by stopping the cell cycle of inducing apoptosis
How is p53 normally regulated?
Typically MDM2 keeps p53 at low concentrations, but under conditions of cellular stress functional p53 will bind to DNA leading to activation of genetic programs arresting the cell cycle, and causing DNA repair or inducing apoptosis
