Cancer Genetics I (Sept. 17 - Schultz) Flashcards
List the 6 oncogenic pathways that lead to tumor growth and malignancy of tumors
- Promote cell division
- inhibit apoptosis
- promote genetic instability
- promote immortality
- promote angiogenesis
- promote metastasis
Describe the concept of cellular immortality
Normal cells have a finite # of cell divisions (30-35 generations) -> then cells go into senescence
Cancer cells will never go into senescence -> gives rise to the term immortality ->overexpression of telomerase (telomers never become short as they produce successive generations) -> immortal cell lines
What are the developmental pathway abnormalities that can lead to cancer?
Mutations in signaling pathways:
- Notch
- Wnt
- Hedgehog
List the 5 tumor suppressor gene pathways:
- Inhibit cell division
- Promote Apoptosis
- Inhibit immortality
- inhibit angiogenesis
- inhibit metastasis
Describe the effects of protease activation (caspases) in the the apoptotic pathway of a cell that leads its phagocytosis
Protease activation through death receptor pathway causes:
- Endonuclease activation
- cell surface alteration
- cytoskeletal reorganization
What are the 2 pathways that lead to the caspase cascade
Death Receptor pathway
&
Mitochondrial/ Signal Transduction Pathway
What does complex in the death receptor pathway which promotes caspase cascade?
DISC - Death inducing signaling complex
What causes the DISC composed of?
cytoplasmic adaptor proteins (i.e. FADD)
What procaspase is responsible for causing caspase cascade. (hint: this is activated by the DISC)
Caspase 8
What is the Death receptor pathway activated by?
TNF alphas -> FAS ligands
What is the difference between the extrinsic and intrinsic death pathway?
Extrinsic pathway is induced through death receptor pathway (neighboring cells secreting TNFs or GF withdrawal) -> extracellular ligands
Intrinsic pathway is induced through mitochondrial signal transduction pathway -> internal regulation/stress
What are the some of the factors that stress a cell and can induce intrinsic apoptotic pathway. (List of 5)
- DNA damage
- mitotic catastrophe
- short telomeres
- high Ca2+
- oxidants
How is mitochondria death pathway induced?
Bak/Bax proteins activate
What occurs once the Bak/Bax proteins are activated and how does the mitochondria pathway cause apoptosis?
Activation of Bak/Bax damage mitochondrial membrane and release cytochrome C -> activates caspase 9 -> induces caspase cascade
What is the function of Apaf1?
Apaf1 is an adaptor protein which works with cytochrome C to cleave caspase 9 and activate it.
What is the complex of mitochondrial death pathway called?
Apoptosome
True or False: Bcl-2 inhibits membrane damage and cytochrome C secretion from mitochondria.
True.
Bcl-2 inhibits membrane damage and cytochrome C passage into cytoplasm
What are the anti-apoptotic dimers?
Bcl-2; BCl-X-like + Bak; Bax
What are the pro-apoptotic dimers?
Bax/Bak oligomers
How does the mitochondria switch to induce pro-apoptotic factors?
Bid; Bad
Compete for Bcl-2 causing dossication of Bak and Bax from Bcl-2.
What is the inhibitor of inhibitor pathway? (Hint: Think about this devil of a protein)
Smac/Diablo
What is XIAP?
X-linked Inhibitor of apoptosis (inhibit caspase 3)
True/False: XIAP is not normally found present in the cytoplasm
False; normal levels of XIAP are found in cytoplasm. They work to inactivate caspase 3
How are Smac/Diablo and XIAP related?
Smac/Diablo production inhibits XIAP which allows activation of caspase 3 and create apototic causing substrates
