Pathoma Chapter 3D Flashcards
Knudson two-hit hypothesis
both copies of the p53 gene must be knocked out for tumor formation, Both copies of Rb gene must be knocked out for tumor formation
Loss of p53 is seen in what percentage of cancers?
>50% of cancers.
p53 Germline mutation results in
Li-Fraumeni syndrome (2nd hit is somatic),
Li-Fraumeni syndrome is characterized by?
the propensity to develop multiple types of carcinomas and sarcomas,
Rb
regulates progression from G0 to S phase.
How does Rb regulate the progression to S phase?
holds the E2F transcription factor, which is necessary for transition to the S phase
E2F is released when?
RB is phosphorylated by the cyclinD/cyclin-dependent kinase 4 (CDK4) complex
Rb mutation results in
constitutively free E2F, allowing progression through the cell cycle and uncontrolled growth of cells.
Sporadic mutation
(both hits are somatic) and it is characterized by unilateral retinoblastoma
Rb Germline mutation results in
familial retinoblastoma (2nd hit is somatic) and is characterized by bilateral retinoblastoma and osteosarcoma.
What is the function of regulators of apoptosis?
Prevent apoptosis in normal cells, but promote apoptosis in mutated cells whose DNA cannot be repaired (e.g Bcl2)
Bcl2
normally stabilizes the mitochondrial membrane, blocking release of cytochrome c
Disruption of Bcl2 allows what to happen?
Cytochrome c to leave the mitochondria and activate apoptosis
Bcl2 in follicular lymphoma?
it is overexpressed in follicular lymphoma,
Why is Bcl2 overexpressed in follicular lymphoma?
t(14;18) moves Bcl2 (chromosome 18) to the Ig heavy chain locus (chromosome 14), resulting in increased Bcl2.
How is apoptosis inhibited in follicular lymphoma?
Mitochondrial membrane is further stabilized by overexpressed Bcl2, prohibiting apoptosis.
In follicular lymphoma, how does the inhibition of apoptosis lead to lymphoma?
B cells that would normally undergo apoptosis during somatic hypermutation in the lymph node germinal center accumulate, leading to lymphoma.
What is necessary for cell immortality?
Telomerase
Normally telomeres do what?
shorten with serial cell divisions, eventually resulting in cellular senescence
What is the relationship between cancers and telomerase?
cancers often have up regulated telomerase, which preserves telomeres
Angiogenesis and tumors
(production of new blood vessels) is necessary for tumor survival and growth.
FGF and VEGF
(angiogenic factors) are commonly produced by tumor cells.
Tumor survival and the immune system?
Avoiding immune surveillance is necessary for tumor survival
Immune surveillance and tumor survival?
Mutations often result in production of abnormal proteins, which are expressed on MHC class 1, CD8+ T cells detect and destroy such mutated cells, Tumor cells can evade immune surveillance by downregulating expression of MHC class 1.
