Neoplasia - oncogenes and tumor suppressor genes Flashcards
“governor” of the cell cycle
RB:
Tumor Suppressor Gene
inhibitor of cell cycle progression
RB function
inhibitor of G1/S transition
RB protein
Retinoblastoma protein
RB familial syndromes
Familial B/L retinoblastoma syndrome (retinoblastoma, osteosarcoma, etc)
RB sporadic cancers
- U/L Retinoblastoma
- Osteosarcoma carcinomas of breast, colon, lung
Tumor Suppressor genes
Loss of function (can’t stop growth)
Need BOTH ALLELES KO
Oncogenes
Gain of function (abnormal growth)
Need ONE ALLELE to be KO
proto-oncogene
Normal genes that regulate cell cycle and proliferation
E7 viral oncoprotein
HPV Inactivates Rb (>>Rb cannot bind to E2F >> progress thru G1/S>>uncontrolled growth)
“guardian of the genome”
TP53:
Tumor Suppressor Gene
enables genomic stability - regulates cell cycle progression, DNA repair, cell senescence, apoptosis
TP53 protein
p53 protein
TP53 function
Responses to DNA damage or hypoxia:
- senescence
- cell cycle arrest at G1 for DNA repair *
- apoptosis
TP53 familial syndrome
Li-Fraumeni syndrome (diverse cancers)
TP53 sporadic cancers
most human cancers - most frequently mutated gene in cancer
APC gene
tumor suppressor gene
inhibitor of mitogenic signaling pathways
THINK - colonic neoplasia
APC protein
adenomatous polyposis coli protein
APC function
degrades B-catenin to inhibit WNT signaling (decrease proliferation)
APC familial syndrome
familial colonic polyps and carcinomas
APC sporadic cancers
carcinomas of stomach, colon, pancreas, melanoma
THINK - Colon Cancer: APC KO (increased polyp risk)»_space; K-RAS KO (formation of polyp)»_space; p53,SMADs/increased COX KO (carcinoma)
VHL gene
tumor suppressor gene
inhibits “pro-growth” programs of metabolism
VHL protein
Von Hippel Lindau (VHL) protein
VHL function
inhibitor/degredation of hypoxia-induced transcription factors (i.e. HIF1-alpha)»_space; for response to hypoxia»_space; increase VEGF and PDGF
VHL familial syndromes
Von Hippel Lindau Syndrome (cerebellar hemangioblastoma, retinal angioma, renal cell carcinoma, pheochromocytoma)
Cerebellar hemangioblastoma
VHL familial
Retinal angioma
VHL familial
Renal Cell Carcinoma
VHL sporadic and familial
VHL sporadic cancer
Renal Cell Carnicoma
Two-hit hypothesis
RB - both copies of gene must be KO
Familial - one already KO, other KO is somatic
Sporadic - both KOs are somatic
pheochromocytoma
VHL
Chromosome 3
VHL
Angiogenesis stimulator, blood vessels
VHL
Governor of cell cycle
RB
Guardian of the Genome
p53
hypophosphorylated RB
How is it inactivated?
hypOp = active. hypERp = inactivated; can be done by HPV E7 binding to active RB
chromosome 17
TP53
E6 viral oncoprotein
HPV,
Inactivates p53
E6 cancers
cervical carcinoma
squamous cell carcinomas of head and neck
hypophosphorylated p53
hpOph = active
p53 and DNA damage cell cycle arrest mechanism
Normal: DNA damage sensed by ATM/ATR kinase-containing complexes»_space; kinases phosph p53»_space; p53 liberated from MDM2 (inhibitor)»_space;
p53 causes p21 transcription»_space; p21 inhibits CDK4»_space; CDK4 maintains RB hypOph»_space; blocks cell cycle
LiFraumeni-Syndrome
inherit one defective copy of TP53
5q21
APC
colonic tumors
70% to 80% of sporadic are APC
WNT and B-catenin
APC, colon cancer
increased levels of angiogenic GF and alterations in cellular metabolism
VHL loss of function mutation
NF1 protein
Neurofibromin-1
NF1 function
Tumor suppressor gene - inhibits mitogenic signaling pathway - inhibits RAS/MAPK signaling
NF1 familial syndrome
NF type1 (neurofibromas»_space;COT» malignant peripheral nerve sheath tumors)
NF1 sporadic cancers (2)
neuroblastoma, juvenile myeloid leukemia
NF2 protein
Merlin
NF2 function
Tumor suppressor gene - inhibits mitogenic signaling pathway - cytoskeletal stability, Hippo pathway signaling
NF2 familial syndromes
NF type2 (benign B/L acoustic schwannoma and meningioma)
NF2 sporadic cancers
schwannoma, meningioma
No merlin
NF2 - cannto est stable cell-to-cell junctions and do not arrest cycle
BRCA1, BRCA2 genes
tumor suppressor genes
DNA repair factors
BRCA1, BRCA2 proteins
Breast Cancer-1
Breast Cancer-2
BRCA1, BRCA2 Function
repair of ds-DNA
BRCA1, BRCA2 familial syndromes
- Familial breast (M/F) and ovarian carcinoma
- Chronic lymphocytic leukemia (BRCA2)
TGF-B function
Tumor suppressor gene
Loss-of-function
Inhibits proliferation
Colon cancer, endometrial, stomach cancer
TGF-B type II receptor
MYC
mutation = oncogene
Transcription factor, gain of function
MYC function
- Activated by RAS/MAPK
- proto-oncogene: activates expression of cell growth genes (D cyclins, rRNA, Warburg); telomerase; reprogram somatic cells into pluripotent stem cells
c-MYC, t(8;14)
Burkitt Lymphoma (ch8)
Burkitt Lymphoma
EBV
t(8;14)
MYC oncogene (c-myc)
n-MYC
neuroblastoma
L-MYC
lung carcinoma
Philadelphia Chromosome
CML
Initiating fusion gene of CML
BCR-ABL
deletion
RB gene (ch13) = retinoblastoma VHL (ch3) = (-) tumor suppresison
BCR-ABL chromosomes
BCR = ch22
ABL=ch9
BCR function and ABL function
BCR function - drives self association of BCR-ABL
ABL function - RTK activity
Cancer associate with BCR-ABL
Chronic Myelogenous Leukemia (CML)