Tumor Suppressor Genes

RSV dominant or recessive

dominant

Fusion experiment

hybrid cell did not form tumors, so it was recessive

tumor suppressor gene functions

negative regulators of cell proliferation

positive regulators of apoptosis

metastasis suppressors

tumor suppressor gene mutations

loss of function

2 types of tumor suppressor genes

Gatekeeper genes- decreased cell proliferation

Caretaker genes- DNA repair and chromosome maintenance

Retinoblastoma

occurs in 1/20,000 infants and children

60% sporadic and 40% familial

Alfred Knudson 2 hit model for retinoblastoma

familial- 1 hit inherited in germline and other hit was somatic mutation in retinal lineage

sporadic- 2 somatic mutations in same cells

RB signal transduction pathway

loss of Rb heterozygosity thru mitotic recombination

mitotic recombination replace normal allele and neighboring chromosomal region with mutant allele and its neighboring chromosomal area

loss of Rb heterozygosity thru gene conversion

DNA strand being elongated during DNA replication temporarily switches templates by leaving its original template strand and forms a hybrid w/ complementary DNA strand belonging to homology chromosome

loss of Rb heterozygosity thru nondisjunction

Gene promotor methylation

Methylating CpG islands inactivates tumor suppressor genes

APC gene and familial adenomatosis polyposis

Hereditary and most sporadic colorectal cancers

APC gene mutation

APC inhibits beta-catenin which activates genes

Mutant APC unable to bind B-catenin to down-regulate its activity

PTEN mutation

PTEN is a tumor suppressor, inhibits AKT precursor

If PTEN mutated, PIP3 rises and AKT increases

haploinsufficiency

inactivation of 1 allele of tumor suppressor gene cannot be compensated by single functional copy

so cell loses ability to control cell proliferation or induce apoptosis (haploinsufficient)

example of tumor suppressor haploinsufficiency

p53

p53 and cancer facts

mutated in 50% of all human cancer and most frequently mutated gene in human cancer

where are most p53 mutations?

In DNA binding domain

what does p16 do

regulates G1/S transition

How is p16 inactivated?

small homozygous deletions

How is p16 silenced?

promoter hypermethylation

LOH in Rb 3 ways

Mitotic recombination

Gene conversion

Nondisjunction

Fusion experiment

Hybrid cells did not form tumors which proved that cancer alleles are recessive