Oncogenes and Tumor Suppressor Genes

Proteins encoded by tumor suppressor genes often:

• control general progression of cell cycle

• act as control proteins of specific cell cycle checkpoints

• transfers or coordinates signals from membrane receptors and cytoplasmic enzymes that inhibit cell growth

• regulates expression of apoptosis-related proteins

• helps repair DNA (enzymatically or recruiting repair proteins or halting cell cycle)

retinoblastoma

rare malignant cancer that develops from cells in retina, occurs in early childhood

• loss of protein function due to gene mutation

• both alleles have to be lost or mutated

What is the generalized function of retinoblastoma gene?

stabilizes p27 → longer half life; binds to some transcription factors + cyclin/CDKS lessening their activity

What is different in mutant retinoblastoma proteins?

• p27 = less stable and cyclin/CDK = more active → more cell cycle progression

• binds to and inactivates pro-apoptotic proteins (so no cell death)

Compare p53 function in normal vs. cancer cells:

• in normal cells: inhibits cell cycle progression, alternating high/low MDM2 levels allow progression/stopping cell cycle by blocking or releasing p53

• mutated p53 in cancer cells: non-functional, cell cycle runs rampant

BRCA susceptibility genes

BRCA1 (chromosome 17) and BRCA2 (chromosome 13); mutation in either increases risk of breast/ovarian/prostrate cancer

Describe BRCA proteins’ normal function:

helps repair DNA breaks by acting as scaffold for repair enzymes (recruits recombinase Rad51)

Rad51

promotes alignment with homologous chromosomes → used as template to repair missing sequence at double-stranded break

Proteins encoded by proto-oncogenes:

• function as growth factors

• serve as receptors for growth factors

• serve as signal transducers for carrying signal from cell membrane to nucleus

• function as transcription factors

• regulate apoptosis

Describe normal c-src functions:

proto-oncogene; attaches to inner cell membrane and has low level of TYR-OH phosphorylation + cell-cycle promoting signals

Describe mutated (activated) c-src functions:

mutation in promoter leads to very high expression of normal src kinase → results in excess phosphorylation and cell cycle promotion

Name src kinase inhibitors:

• bosutinib

• dasatinib

• ponatinib

**can have off-target inhibition of other kinases

Abl oncogene:

specific to chronic myeloid leukemia, located on chromosome 9

• Philly chromosome provides marker of cells and brings together Abl to fuse with BCR on chromosome 22

chimeric BCR-ABL gene

produces hybrid protein with HIGH kinase activity, activates cell cycle promoting signals → drives continuous cell division