Chapter 7 Cancer Biology Tumor Suppressor Genes

LOH's 3 mechanisms

1. Gene conversion 2. Moitic recombination 3. Nondisjuction 4. Hemizygosity

Retinoblastoma

1. sporadic form no family history 2. famillial form which has a parent who suffered from Rb

Caretakers

DNA maintenance; indirectly controlling the rate at which calls accumulate mutant genes

APC

Facilitates egress of cells from colonic crypts; how cells acquire motility; common in colon cancer; associates with beta-catenin together with two scaffolding proteins this forms a multi-protein complex that brings GSK-3B and B-catenin together which leads to the degradation of Beta- Catenin

Mitotic recombination

a recombination occurring between one of the chromatid arms carrying the wild type Rb allele and a chromatid from the paired chromosome carrying the mutated allele; thought to occur during cell proliferation

NF1

acts as a negative regulator of Ras signaling; behaves closely to Rb thus mutant alleles of this gene gets transmitted through the germ line and acts dominant; converted from heterozygous to homozygous; GAP protein which means it sends Ras to its inactive state: common in neurofibromas

Tumor Suppressor genes

anti growth genes; genes that operate to constrain or suppress proliferation

Gatekeeper

directly control how cells proliferate, differentiate, or die; allowing or disallowing cells to progress through the cell cycle

gene conversion

during DNA replication DNA polymerase switched from normal template to mutated template to a hybrid gene results in LOH

polykaryon

giant mutli-functional cell having one extremely large cytoplasm

Haploinsufficiency

half normal dose of NF1 protein results in a clear and aberrant phenotype

Heterokaryon

hybrid cell which carries 2 genetically distinct nuclei

Syncytium

large cell with a single cytoplasm and two nuclei

Nondisjunction

loss of an entire chromosome due to an inappropriate chromosomal segregation during mitosis

CPG

occurs in the vicinity of a gene promoter it can cause repression of transcription of the associated gene and conversely when methyl groups are removed, transcription of this gene is often re-repressed; important in shutting down TSG

Restriction Fragment Length Polymorphism (RELP)

since the allelic versions of this sequence either permitted or disallowed cleavage by a restriction enzyme known as; these are used to determine if a chromosome under went LOH during the development of tumors. They also depend on the detection of single-nucleotide polymorphism(SNPs) in normal and cancer cells

Hemizygosity

the chromosomal arm is only present in only one copy rather than the usual two copies per cell

pVHL

tumor suppressor gene; in mutated form acts as dominant allele; works best under low oxygen areas it is degraded in high oxygen environments