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
