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Learn about the role of oncogenes in stimulating cell division and how mutations lead to excessive cell proliferation. Explore examples like Myc, Ras, and Abl, as well as mechanisms such as chromosomal rearrangements and gene amplification. Discover how oncogenes like c-myc and EGFR are implicated in cancers like Burkitt's lymphoma and breast carcinoma. Gain insights into viral insertions, fusion genes, point mutations, and loss of degradation signals affecting cell cycle control. Explore growth factor signaling interactions and their impact on oncogene expression, providing a comprehensive understanding of the role of oncogenes in cancer biology.
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oncogenes Tumour suppressor genes
Oncogenes • Genes known as proto-oncogenes code for proteins that stimulate cell division • mutated forms, called oncogenes, cause stimulatory proteins to be overactive, with the result that cells proliferate excessively • gain of function mutations
Myc Sis Erb Src Ras Yes Abl Fos jun Myelocytomatosis Simian sarcoma Erythroblastoma Rous sarcoma virus Rat sarcoma 2 viruses Y73 & ESH sarcoma, isolated from a chicken owned by Mr. Esh Abelson murine leukaemia virus Finkel biskis jinkins reilly mouse sarcoma junana Some acronyms!
Activation of proto-oncogenes • Viral insertion • Chromosomal rearrangements • Altered regulation • Fusion genes • Gene amplification • Point mutations • Loss of degradation signals
Chromosomal rearrangements – altered regulation Burkitts lymphoma All patients show t(8:14) translocation of the immunoglobulin gene on chromosome 14 to the c-myc oncogene locus on chromosome 8 c-myc is under regulatory control of IgH resulting in overexpression of the oncogene
Chromosomal rearrangements - fusion gene Chronic Myelogenous Leukaemia Translocation t(9:22) Abl-bcr fusion gene encodes a constitutively active protein tyrosine kinase, which affects cell cycle, adhesion and apoptosis
point mutations Point mutations in ras, implicated in bladder carcinoma e.g. GGC to GTC (G12V)
Gene amplification Metaplastic breast carcinomas (MBCs) account for less than 1% of all invasive mammary carcinomas. Approximately 70–80% of metaplastic breast carcinomas overexpress the epidermal growth factor receptor (EGFR). Human epidermal growth factor receptor (HER2) EGFR gene amplification in MBC (>5 signals per nucleus). Note the bizarre neoplastic cell with more than 10 copies of EGFR.
Loss of degradation signals Epstein–Barr virus (EBV) is a human herpesvirus associated with lymphoid and epithelial malignancies. Three viral proteins, EBNA1, LMP-1 and -2A, constitutively activate c-myc oncogene by decreasing ubiquitin-dependent proteolysis of this protein and upregulate compensatory pathways in Burkitt’s lymphomas. Seminars in Cancer Biology Volume 13, Issue 1 , February 2003, Pages 69-76
Growth factor signalling and oncogenes Cell Cycle Control is through the effects of growth factors which interact with membrane-bound glycoprotein receptors that transduce the message via a series of intracellular signals that promote or inhibit the expression of specific genes.
