Chapter 7 - Tumor Suppressor Genes Flashcards
Tumor Suppressor Genes
AKA TSGs or antigrowth genes – operate, constrain, suppress cell proliferation as counterbalancing mechanism - play a role in tumorigenesis when these genes are inactivated or lost
Syncytium
result of a fusing agent - a large cell with a single cytoplasm and two nuclei, result of contact between two cells and the presence of a fusing agent
Polykaryon
result of a fusing agent - a giant multi-nucleated cell having one extremely large cytoplasm, result of contact between many cells and the presence of a fusing agent
Heterokaryon
result of a fusing agent - a large cell with multiple (usually 2) genetically distinct nuclei, result of contact between two cells of different origin and the presence of a fusing agent
How is cell fusion used to determine the genetic potency/composition of tumorigenic phenotypes contained in cells?
A normal cell is fused with a cancer cell. The result is a hybrid cell that is tumorigenic or non-tumorigenic – where if the cell is tumorigenic, it can be assumed that cancer alleles are dominant.
What is the correlation between virus associated cancers/non-virus associated cancers and dominant/recessive genotypes?
It was common that when cancer cells derived from non-virus associated tumors were fused with normal cells - a non-tumorigenic phenotype was presented. However, when cancer cells derived from virus associated tumors were fused with normal cells - a tumorigenic phenotype was presented. (USUALLY not ALWAYS)
Retinoblastoma
A rare (1 in 20,000) tumor-type associated primarily with children presented in two forms. The first being retinoblastoma of one eye - where no family history of retinoblastoma is presented. This form is known as SPORADIC or UNIlateral retinoblastoma. The second type is usually presented in both eyes and is common when there is a family history of retinoblastoma. This form is known as FAMILIAL or BIlateral retinoblastoma.
Cause of Retinoblastoma
Defects in the Rb gene (A known tumor suppressor gene) where in familial retinoblastoma one allele possess the mutant Rb allele (hypothetically either inactive or lost) requiring only one somatic mutation to the other allele to result in bilateral retinoblastoma. In sporadic retinoblastoma neither copy of the Rb allele possess a mutation, requiring two somatic mutations, one to each allele to result in unilateral retinoblastoma.
Enterocytes
Specialized small intestine cells, highly differentiated epithelial cells that may participate in processes such as absorbing nutrients from the lumen and transferring these nutrients to circulation or absorbing water, or secreting mucin helping to protect colonic epithelium from lumen contents
Loss of Heterozygosity (LOH) by Mitotic Recombination
May be a result of MITOTIC recombination where loss of a gene on one chromatid is reflected on the other after recombination - After G2 and within the M phase, after chromosomal duplication - the mutant gene is replicated and recombined with chromosome with the wild type allele - forming two chromosomes both with the mutant gene.
LOH by Gene Conversion
During DNA replication of S Phase, DNA polymerase jumps between copies of homologous chromosomes, where in the case of Rb – DNA polymerase may jump from the template having the wild type allele to the mutant - resulting in a new strand that will have that mutant allele **More common than mitotic recombination
LOH by Hemizygosity
a portion of a chromosome (a gene) may be deleted and not replaced by a copy of the homolog - resulting in only one allelic copy of that gene available
LOH by Nondisjunction
a result of improper chromosomal separation during anaphase of M-Phase of the cell cycle where only one chromosomal copy is present in the daughter cell = only one allele is present in the new cell
As rare as mutations are - what accounts for the two consecutive random mutations that lead to unilateral (sporadic) retinoblastoma?
Rather than two consecutive gene knock-out mutations of Rb occurring, it is more likely that one mutation results in LOH by some mechanism of recombination, copying error, or separation error during M-Phase leading to a cell’s dependency on the mutant allele
VHL
Von-Hippel Lindau Gene – one known function of pVHL (product of the VHL gene) is the destruction of the HIF-2 transcription factor
Why are mutant tumor suppressor genes transmitted through the germ-line in contrast to mutant proto-oncogenes - which are usually not?
Most oncogenic phenotypes during embryonic development result in an unviable embryo due to the fact that most oncogenes act dominantly and disturb individual cells during fetal development - where as tumor suppressor mutations are typically recessive and only appear later after multi-step tumorigenesis - loss of tumor suppressor genes is usually not enough to result in tumor formation.
Promoter Methylation
CpG methylation when either in the vicinity or acting upon a gene promoter may result in the inactivation or suppressed transcription of that gene – methylation may play a role similar to mutation in inactivating tumor suppressor genes leading to tumorigenesis
NF1
A tumor supressor gene that encodes a Ras-GAP (Ras-inactivating) that is shown to be commonly mutated allowing overactivation of Ras – leading to cancer cell behavior
Haploinsufficiency of TSGs
In some cases, LOH is not required to result in abnormal cell phenotype - heterozygosity alone where only one mutant allele is present is in some cases enough to result in altered cell behavior e.g. NF1 haploinsufficiency in mast cells/LOH schwann cells may result in neurofibroma
B-catenin ACTIVE function
In the presence of the Wnt signal, the receptor recruits the dishevelled protein as well as axin sequestering axin to the cell membrane – results in the ceased phosphorylation of B-catenin by GSK-3B and subsequent degradation of B-catenin who now freely associates with Tcf/Lef proteins and acts as a transcription factor leading to active cell proliferation
What signaling cascade and protein plays a role in the formation of adenomatous polyps in the colon aka FAP?
B-catenin:Tcf/Lef results in over-proliferation and polyp formation OR mutation of APC results in decreased degradation of B-catenin
B-catenin INACTIVE function
When Wnt signals are not stimulating the pathway - a complex of Axin and APC activate GSK-3B which actively phosphorylates B-catenin for recognition for degradation
What is the purpose of the intestinal crypts?
Crypts shield enterocyte stem cells from the contents of the intestine - protecting newly born enterocytes during their growth and differentiation
Sporadic VHL inactivation
associated with 70% of sporadic (non VHL disease associated) kidney cell carcinoma and inactivation is observed as a result of promoter methylation!!!!
VHL Disease
a familial cancer syndrome acting in an autosomal dominant fashion when VHL is germ-line mutated - often correlated with pheochromocytomas (kidney cell carcinoma) and hemangioblastomas (blood vessel tumors) of the CNS and retina
HIF-2
stands for HYPOXIA-INDUCIBLE FACTOR-2 which is associated closely with HIF-1 and HIF-3 of which HIF-1 specifically is known most about in terms of its biochemical behavior - made up of an alpha and beta subunit
HIF-1
under normoxia - pVHL promotes HIF1a subunit degradation resulting in noncombination of the alpha and beta subunits and no transcription occurs. Under HYPOXIA - HIF1a is no longer degraded, binds to the beta subunit and results in the transcription of genes that are involved in angiogenesis, erthyropoiesis, glycolysis, increased glucose transport into the cells (increased number of glucose pumps) [glycolysis and glucose transport fostering aerobic glycolysis] - enabling cells to survive under hypoxic condidtions
HIF-1 Angiogenic Response
induces transcription of genes including VEGF, PDGF, and TGF-a, EPO
VEGF
Vascular endothelial growth factor – attracts and stimulates growth of endothelial cells that construct new blood vessels
PDGF
Platelet derived growth factor – stimulates further endothelial cell growth for the construction of blood vessels as well as associated mesenchymal cells (including pericytes and fibroblasts)
TGF-a
Transforming growth factor a - stimulates a wide variety of cells towards blood vessel construction including epithelial cells
EPO
erythropoitin – increased levels in the blood lead to red blood cell production in the bone marrow
What is the significance of a neoplastic phenotype being most commonly recessive?
the expression of the neoplastic phenotype depends in part on the inactivation of TSGs - meaning that the loss of genetic information is critical in the role of tumor development
How do we know that the inactivation or loss of TSGs is what plays a role in tumor development?
TSGs are usually present in the genomes of cancer cells but as inactive alleles demonstrating the significance of inactivating functional genetic material
What is the significance of LOH to tumor development?
Where only one allele may contain a mutation or inactivation of a gene (heterozygosity acts as a form of prevention) - in order for the development of a tumor to ensue - loss of heterozygosity or total loss of function must first be the result in a certain tissue type. Heterozygosity prevents every tissue type from developing neoplasia
How does loss of a TSG occur?
Either through a genetic (somatic) mutation resulting in the loss of inactivation of that gene or via silencing of that gene by promoter methylation
What mechanisms play a role in the potential LOH?
mitotic recombination, gene deletion (loss of a chromosomal region) inappropriate chromosomal segregation (nondisjunction), gene conversion (jumping DNA polymerase)
Why is LOH more common than only the rate of random mutation?
Inactivation of one copy of a TSG may be followed by a mechanism that facilitates the loss of the other copy apart from mutation (see mechanisms of LOH)
What is the frequency of a LOH event and how does it compare to methylation and mutation in terms of inactivating a TSG?
LOH events are more frequent and also vary in frequency based on the gene
If tumors are arising in one individual based on changes to the same chromosomal region in different tissues, what does this indicate?
Indicates the presence of a TSG in that chromosomal region
What is the only commonality in mechanism between the loss of various TSGs?
the loss of a TSG increases the likelihood of neoplastic cell transformation and/or progression of that cell to a malignant state
What is the result of the loss of a TSG in a germ line?
This loss may be passed between generations - increasing the likelihood of this germ cell line (between generations) to develop various cancers that are similar between each inheritance
What is another name for TSGs and why were they given this name?
“Gatekeeper genes” are involved in deciding the rate of cell proliferation
Are TSGs the same as “Caretaker genes”?
No, though the loss of these genes acts similarly in the loss of TSGs rather than the activation such as with oncogenes - caretaker genes are involved in maintaining the integrity of the genome
