Tumor Suppressor Genes
__(A)__ critical for triggering degradation of B-catenin. Cells lacking ___(A)__ have shown to have an increase in ___________. Can lead to accumulation of too many chromosomes Loss of this can lead to ________, or incorrect number of chromosomes due to improper advantages in some cells
APC, chromosomal instability (CIN), aneuploidy
__________________ is a tumor suppressor, frequently associated with colon cancer, and is associated with an inherited susceptibility to develop colon polyps. Also called _________________.
Adenomatous polyposis coli (APC), familial adenomatous polyposis (FAP)
_________ gene: ___________ of this gene is associated with breast cancer risk, and to a lesser extent, with ovarian cancer. Found to be inactive in 10-15% of __________ breast carcinomas, but always through methylation, not deletion or mutation
BRCA1, inactivation, sporadic
_______________ contains the replicating stem cells near the bottom--cells further up are more differentiated with specialized functions. Stem cells are protected in the _____ area.
Colonic crypt, crypt
Some regions contain __________, large amounts of CpG areas that are methylated. ____________ tumor suppressor gene was found to be hypermethylated on this in its promoter in solid tumors
CpG islands, RASSF1A
Promoter methylation happens in promoter on ___________ residue.
Cytosine-guanine (CpG)
[Promoter methylation] _______________ adds new methyl group to recently synthesized daughter strands after replication. May involve __________ to the sites of methylated CpGs, which then removes acetate groups from the side chains of AA on _______ molecules in the nearby chromatin (favoring transcription-> inhibiting transcription)
DNA maintenance methylase, histone deacetylases (HDACs), histone
________ is used as a marker for Rb. Located in the ______ chromosomal region. Conduct ______ to identify isoform A/B in normal and tumor tissue in patients
Esterase D, 13q14, electrophoresis
______________ is a _______ cancer associated with the development of benign tumors of the cell sheaths around nerves Occasionally becomes malignant: ____________ Increased risk in tumors of astrocyte lineage in the brain, in the adrenal glands, and in the bone marrow
Neurofibromatosis 1 (NF1), familial, neurofibrosarcomas
____ is used as a newer way to find regions of frequend LOH
PCR
__________ converts one or both prolines on HIF-1a to _____________, which enable the binding of HIF-1a to ___.
Proline hydroxylase, hydroxyproline residues, VHL
Tumor suppressor genes can be identified by mapping _________ (SNPs found within a restriction site)
RFLPs (restriction fragment length polymorphisms)
NF1 i a ________, ___________ is the region that contacts Ras, fits into a cleft, and contributes to GTP hydrolysis. Lack of NF1=Ras is _____
Ras GAP, arginine finger, active
__________ is one of the most well known oncogenes and involves single point mutation. Once activated, can activate multiple pathways in the cell, many of which are involved in cell growth, proliferation, and cell cycle progression
Ras oncogene
______, a tumor suppressor genes implicated in stomach cancer, is almost always inactivated by methylation and not by mutation or deletion
Runx3
________: HDAC inhibitor that reverses deacetylation and thereby reverts the chromatin to a state that favors transcription Treatment of breast cancer cells with this can restore sensitivity to ____
Trichostatin A (TSA), retinoic acid (RA)
__________________ is associated with mutations in VHL tumor suppressor gene
Von Hippel-Lindau Disease (pVHL)
[Adenomatous polyposis coli] _____ is the ligand _____ is the receptor _____ is the proliferation promoting factor
Wnt, Frizzled, B-catenin
Patients of NF1 show "___________", which are areas of hyperpigmentation of skin, and benign region of the ____. ________ that wrap around peripheral axons are probably the source of these growths
cafe au lait, iris, schwann cells
___________________ provided the first clues for presence of tumor suppressor genes
cell fusion experiment
[Adenomatous polyposis coli] when the receptor is not bound with Wnt: Inactive ___________ Active _______ complex with ____, ____, and __(A)___. __(A)__ degraded via ________. No proliferation
disheveled protein (DVL), GSK-3B, axin, APC, B-catenin, proteasome
Methylation is considered ________--heritable trait, but does not alter nucleotide sequence of the DNA
epigenetic
______ retinoblastoma: family history, multiple bilayer tumor Even after treating the tumor, the patient has great increased risk for cancer--usually ______
familial, osteosarcomas
[Cell fusion experiment] when cells growing adjacent to each other in culture are exposed to a _________ agent (_________ or _________), they form a _________ with two nuclei
fusogenic, Sendai virus, polyethylene glycol, heterokaryon
__________: occur during DNA replication (S phase); gene forms a hybrid with the complimentary DNA on the homologous chromosome; leads to loss of heterozygosity
gene conversion
__________ occurs when one allele is missing
hemizygosity
Main function of VHL is to foster destruction of a subunit of a transcription factor called ______________________
hypoxia-inducible factor 1 (HIF-1)
______ is a mutant (activated) or overexpressed version of the proto-oncogene, found in cancer. Mutation on one allele is sufficient to cause cancer
oncogene
____, a tumor suppressor gene, was found to be methylated in 44% of normal bronchial epithelial cells cultured from current and former smokers
p16
[Target genes that HIF-1 activates] ____: stimulates cells important for blood vessels
platelet derived growth factor (PDGF)
___________: type of heterokyron with more than two nuclei; usually cannot proliferate
polykaryons
____________: mechanism for inactivation of tumor suppressor genes in addition to LOH Gene sequences appear normal but inactivates gene at _______ by ______.
promoter methylation, promoter, methylation
_______ is a normal cellular gene that is associated with cancer only if it is improperly activated (usually by overexpression, mutation, or gene translocation)
proto-oncogene
_____________: first tumor suppressor genes discovered; loss of chromosomal material at _______
retinoblastoma (Rb), 13q14
_________: potent inducer of cell cycle arrest in many epithelial cells In many cases, the gene for _________, which encodes this receptor is silenced due to methylation-> unresponsive
retinoic acid (RA), RARB2
Methylation specific PCR: treatment with _______ under _____ conditions convert ________ cytosines to _______, while leaving ________ Cs untouched
sodium bisulfite, alkaline, non-methylated, uracil, methylated
_______ retinoblastoma: no family history; single unilateral tumor
sporadic
[colonic crypt] Enterocyte stem cells encounter Wnt factors released by _______ cells near the bottom of the crypt-> keeps ______ level high in cells-> held in stem cell like states
stromal, B-catenin
[Target genes that HIF-1 activates] _____: stimulates growth of a variety of cell types including epithelial cells
transforming growth factor alpha (TGF-a)
________only causes cancer if it is inactivated or deleted. Mutations must occur on both alleles to cause cancer
tumor suppressor gene
VHL tags HIF-1a by _________ and targets it for destruction (requires ATP)
ubiquitylation
[Target genes that HIF-1 activates] _____: causes growth of endothelial, or blood vessel, cells
vascular endothelial growth factor (VEGF)