Protooncogenes are Dominant: 1 mutant allele needed (ret, ras, abl, myc, Cyclin D)
Antioncogenes are Recessive: both alleles must be mutated (Rb, p53, APC, WT-1, BRCA, p16, NF-1)
Apoptosis genes: bcl-2 (inhibits), bax, bad (promote)
Gene amplification: Double minutes or HSR. In N-myc (neuroblastoma) or c-erb B2/her-2-neu (breast) indicate poor prognosis.
abl – non-receptor tyrosine kinase
APC – signal transduction
bcl-2 – located in outer mitochondrial membrane, er, and nuclear membrane; believed to prevent exit of cytochrome c from mitochondria.
BRCA – DNA repair; rare in sporadic breast cancer. 80% of familial breast ca. though familial is 5-10% of total breast ca.
Both increase risk of ovarian ca; BRCA1 increases risk of prostate and colon; BRCA2 increases risk of male breast ca.
NF-1 – signals ras
ras – GTP binding protein, single most common abnormal oncogene in human tumors (10-20% all tumors), protein binds GTPase activating protein (GAP); mutant ras leaves GAP in permanent “on” position.
Rb – cell cycle regulator; active underphosphorylated form stops G1 – S by binding/sequestering E2F transcription factors; hyperphosphorylated is inactive;
Four genes regulate phosphorylation of Rb: Rb, cyclin D, cdk4, p16(aka ink4) which inhibits cdk4.
E7 protein of HPV binds and inactivates Rb.
p53 – cell cycle regulator; single most common target for genetic alterations in human tumors. Radiation and chemo mediate their effects through p53. E6 protein of HPV inactivates p53.
actions of p53: growth arrest without damage
· induces cdk inhibitor p21
· if repair successful, induces mdm2, which downregulates p53
· if repair unsuccessful, induces apoptosis genes
Tumors and Cell Cycle:
Oncogene mutations allow cells to go into G1-S more easily than normal; Not usually associated with a shortened cell cycle time.
Cyclins: control transition from G1 – S; Cyclin D (mantle cell t(11,14)(q13q32), Cyclin E
cdks: cdks 2 binds Cyclin E; 4 & 6 bind D