Cancer I Flashcards
Define whether a gene that regulates cell division, immortality, apoptosis, angiogenesis, or metastasis is an oncogene or a tumor suppressor gene.
Its actually both. They both regulate these properties but in different ways.
An oncogene would promote cell division, immortality, angiogenesis, and metastasis while inhibiting apoptosis.
A tumor suppressor gene would promote apoptosis while inhibiting cell division, immortality, angiogenesis, and metastasis.
Explain how oncogenes act in a dominant fashion while tumor suppressor genes act in a recessive fashion.
Oncogenes act in a dominant fashion because you only need one mutation in order to lead to an amplified cell cycle which could lead to cancer.
Tumor suppressors act in a recessive fashion because loss of one tumor suppressor gene does not cause any differences, you have to lose both genes (alleles) in order for it to lead to cancer.
Extrinsic Pathway
Death Receptors. Fas death ligand binds the Fas death receptor which leads to the binding of either FADD or TRADD. This binding leads to the binding of the caspase 8 at the death effector domain (both FADD/TRADD and caspase 8 has a death effector domain so there is some dimerization), the caspase 8 is then cleaved, leaving the death effector domain behind and is now activated. It now has the ability to activate (through cleavage) the effector caspases which cleave/activate things such as Phosphotityl serine signal, endonucleases, and the change of the cytoskeleton structure which leads to apoptosis and then the eventual phagocytosis of the dead cell.
Intrinsic Pathway
Mitochondrial dependent. Lack of growth factors leads to an apoptotic signal. This signal induces the expression of BH3-only proteins which blocks Bcl2-anti-apoptotic factors and enhances Bax, Bak (Bcl2 effectors). This leads to the stimulation of the mitochondria to release cytochrome C. Cytochrome C binds to APAF1 which undergoes a conformational change in order to bind to CARD. This then forms a 7 membered ring structure known as the apoptosome. The apoptosome interacts with caspase 9 through the CARD domains (both of them have them). Eventually caspase 9 is activated through cleavage (mechanism is not fully understood) and then it goes on to form effector caspases which cleave and initiate things such as the Phosphotityl serine signal, endonucleases, and the change of the cytoskeleton structure which leads to apoptosis and then the eventual phagocytosis of the dead cell.
Other proteins released from the mitochondria
SMAC is released which causes the inactivation of effector caspases through the inactivation of X1AP so that the cell does not undergo apoptosis.
Understand the mechanism of caspase activation
The caspase is formed by an apoptotic signal interacting with adaptor proteins by activating them. The initiator caspase forms a dimer- they activate each other, which then allows them to bind to the executioner caspase through cleavage of the fully active caspase and then it can cleave multiple substrates which leads to apoptosis.
Describe increased production of anti-apoptotic Bcl2 family protein
A survival factor binds a receptor which leads to the upregulation of the Bcl2 and Bclxl proteins which blocks apoptosis.
Describe the inactivation of pre-apoptotic BH3-only protein
A survival factor binds a receptor which leads to the activation of a kinase, this kinase then phosphorylates the BH3-only protein that is bound to a Bcl2-anti-apoptotic protein and therefore releases this protein and becomes inactive so that the Bcl2 family can inhibit apoptosis.
Describe the inactivation of anti-IAPs
A survival factor binds a receptor which initiates the MAPK through a series of phosphorylation (signal transduction cascade). MAPK phosphorylates Hid (which usually serves to inhibit IAPs in order to promote apoptosis). When Hid is phosphorylated it no longer binds to IAPs which makes the IAPs active and blocks apoptosis.
Carcinoma
Cancer of the epithelial cells
Sarcoma
Cancer of the connective tissues and muscle cells
Leukemia/Lymphoma
Cancer of the blood-specifically WBCs
Describe the steps and barriers to the metastatic process
This includes the invasion of local tissues, movement through the circulatory system , leaving the vessels, establishing new cellular colonies at distant sites. The initial invasiveness is very difficult but after that it is easier, until it wants to colonize a remote site, and then it is difficult for it to survive, grow, and continue to proliferate.
Explain the role of laminin receptors in the three-step mechanism for basement membrane invasion by tumor cells.
MET cells bind to the laminin on the basal lamina, the membrane is then degraded by type IV collagenase and the cell can now move through the basal lamina.
How is invasion in angiogenesis by non-transformed endothelial cells is similar to invasion by metastatic cells
In angiogenesis the endothelial cells release proteases to degrade the basal lamina- which is similar to what the metastatic cells does through the binding of laminin. Both leads to the tumor cells being able to invade.
