Transcript oncogenes
Oncogenes and tumour suppressor genes 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 Oncogenes gain of function mutations Some acronyms! • • • • • • 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 Activation of proto-oncogenes • Viral insertion • Chromosomal rearrangements – Altered regulation – Fusion genes • Gene amplification • Point mutations • Loss of degradation signals Viral insertion 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 cmyc oncogene by decreasing ubiquitindependent 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. Oncogenes and the cell cycle GENES Further examples of oncogenes Genes for growth factors or their receptors PDGF Codes for platelet-derived growth factor. Involved in glioma (brain cancer) erb-B Codes for the receptor for epidermal growth factor. Involved in glioblastoma (brain cancer) and breast cancer erb-B2 Also called HER-2 or neu. Codes for a growth factor receptor. Involved in breast, salivary gland and ovarian cancers RET Codes for a growth factor receptor. Involved in thyroid cancer Genes for cytoplasmic relays in stimulatory signaling pathways Ki-ras Involved in lung, ovarian, colon and pancreatic cancers N-ras Involved in leukemias Genes for transcription factors that activate growth promoting genes c-myc Involved in leukemias and breast, stomach and lung cancers N-myc Involved in neuroblastoma (a nerve cell cancer) and glioblastoma L-myc Involved in lung cancer Genes for other molecules Bcl-2 Codes for a protein that normally blocks apoptosis. Involved in follicular B cell lymphoma Bcl-1 Also called PRAD1. Codes for cyclin D1, a stimulatory component of the cell cycle clock. Involved in breast, head and neck cancers MDM2 Codes for an antagonist of the p53 tumor suppressor protein. Involved sarcomas (connective tissue cancers) and other cancers References