Caroline Speed; Week 8 MED1011; Biochemistry
Oncogenes are altered forms of regular genes that promote cell growth. Proto-oncogenes are normal genes that promote cell growth and division, are important for survival, growth, development and differentiation, and are mutated to form oncogenes. Include growth factors, growth factor receptors, intracellular signalling proteins, transcription factors and cell cycle control proteins. Can become oncogenes by activating mutation in DNA coding sequence, gene amplification, chromosomal translocation. Oncogenes have gain of function mutation in a single copy of cancer critical gene that can predispose to cancer. Tyrosine kinases regulate cellular proliferation, survival, differentiation, function and motility. Ras/Map signalling pathway activates transcription factors. Tyrosine kinase receptors autophosphorylate to initiate intracellular signalling cascade, regulated by ligand binding forming dimer, receptors cross phosphorylate each other. Tyrosine phosphorylation is a switch to trigger assembly of signalling complexes, relays signals to the nucleus.
Src non receptor tyrosine kinases more active in colon cancer, Akt and PDK serine threonine kinases are active in breast and ovarian cancer, receptor tyrosine kinases all others. CML has 9:22 translocation, diagnosis depends on chromosomal translocation detected by cytogenetics, FISH or PCR. Abl is widely expressed and is essential for normal development, when overexpressed it usually inhibits cell cycle progression but when fused to BCR it causes increased cell growth and inhibition of cell death.
Chemotherapy, surgery and targeted therapies are used. Major new therapies are targeted against tyrosine kinases. Is complementing chemotherapy and giving hope for curing incurable cancer. These include ATP competitive inhibitors, antibodies against tyrosine kinase and their ligands., antibodies against receptor tyrosine kinases and their ligands, anti-angiogenics