Chok Biochem 3rd Shift Reviewer Onco

ONCOGENES

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Cancer – disease in which cells grow abnormally, disorganized and unresponsive to normal growth restraints Oncogenes – genes that cause a cell to become cancerous; code for production of proteins involved in growth control Proto-oncogenes – genes that regulate normal cell proliferations, codes growth-controlling proteins, transformable to oncogenes

Classes of Growth Controlling Proteins Class Description polypeptide hormones (eg. EGF, IGF, TGF, CSF, PDGF), pure Growth factors signals, no metabolic purpose Growth factor receptors

cell-surface or intracellular, sensitive to the signal

2nd messengers, cytoplasmic or plasma membrane proteins that transmit signals from receptor to cellular target; allows new gene expression, or modifying levels of expression, largest class of oncogenic proteins

Intracellular transducers

Nuclear transcription factors and nuclear membrane proteins

directly affect nuclear functions [transcription]; might be involved in RNA splicing; bind to DNA secquences in promoters and enhancers of genes

Example sis = platelet-derived GF = simian sarcoma virus (sv40) Surface: fms (CSF-1), erb-B (EGF), neu (EGF-related), ros (insulin-like GF) Nuclear: erb-A (thyroid hormone receptor-like) Protein-tyrosine kinase – src, abl, fps/fes serine/threonine kinase – raf, mos ras-proteins / GTP-binding – GTP proteins with GTPase activity (Haras, Ki-ras, N-ras) PLC-related protein – contains srcrelated regions homologous to PLC (crk) jun, fos, N-myc, myb, p53, ski

Sites of Oncogenic Intervention / Mimicry of Growth-Control Proteins 1) Protein itself as a mimic – interaction with suitable receptor = cell growth (autocrine fashion) 2) Mutation of occupied GF receptor – mitogenic signal even without exogenous stimuli 3) Act on intracellular growth control pathway – no need for exogenous stimuli Protooncogenic Activation Mechanisms Mechanis Description m causes excessive Point expression or mutatio abnormal protein n synthesis Genetic rearran proximity of gement chromosomal / breakpoints to Chrom known loci of osomal oncogenes translo cation increase number in Gene gene copy number amplific leads to overation expression gene Promot rearrangement er and causes enhanc protooncogene to er be enhanced or insertio fused with another n gene Deletio n of loss of genes tumor whose expression suppre inhibits ssor transformation genes / leading to antineoplastic oncoge conversion nes Causes of Activation Cause Radiation Chemicals Carcinogens Others Viruses RNA Tumor/ Oncorna Viruses Tumor Viruses

Examples

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ras family – difference in 12th codon (Gly  Val) = oncogene product p21 protein – role in cellular responses to hormones and drugs  ↓ GTPase activity implicated with epithelial tumors, sarcomas, erythroleukemia Burkitt’s lymphoma: c-myc from Chr8  Chr14 = enhanced heavy chain immunoglobulin production Chronic myelogenous leukemia: c-abl from Chr9  inserts into bcr gene @ Chr 22  bcr-abl hybrid gene (Philidelphia chr)  growth of leukemia cells

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Neuroblastoma – N-myc gene with replication errors

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myc gene – activated by upstream insertion of viral LTR (promoter) or by up/downstream insertion of provirus in myc in reverse direction (enhancer)

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Retinoblastoma – deletion of RB gene in Chr 13 Colorectal cancer – deletion of p53 (guardian of the genome, controls apoptosis) in Chr17

Effect breaks DNA strands Electrophillic reactivity  attack DNA affinity for proliferating cells interferes with DNA replication & repair integrates own DNA with host DNA retroviruses, single stranded DNA genome, reverse transcriptase

Examples UV, X-ray, atomic particles Natural or man-made; food and chemical pollutants Aflatoxin – moldy peanuts Benzopyrene – grilled foods Diethylnitrosamine – whiskey Vinyl chloride – plastic drugs, chemotherapeutics, repeated trauma RNA / DNA tumor viruses HTLV, HIV

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Rous sarcoma virus – in chickens, retrovirus Contains oncogene src + 3 genes in retroviruses o gag – viral core proteins o pol – reverse transcriptase and integrase o env – surface (envelope) glycoproteins retroviral oncogenes (v-src) has cellular counterparts (c-src) with introns = v-src probably obtained from host cells intronless RNA genome replicates via reverse transcription into DNA, proviral DNA integrates into host genetic material  transcribed if inserted near oncogene of host  oncogene becomes part of retroviral genome  transcribed and propagated LTRs (long terminal repeats) – 100-200 base pairs at ends of inserted proviral segment serve as molecular control elements in activation of cellular oncogene  Retrovirus family – adult T-cell leukemia / lymphoma (Human T-lymphocyte virus); Kaposi’s sarcoma (HIV) Polyoma viruses, adenoviruses, HepaB virus, Epstein-Barr virus Propagated in the wild, not dependent in cancer production o SV40 virus – activates host cell for DNA replication  uses host proteins to replicate and transcribe its own genome Viral DNA, if it failed to replicate, may act as an oncogene, stably incorporated into host genome Viral DNA protein products can deactivate tumor suppressor genes (T antigen with RB protein gene) No cellular counterparts  Papiloma virus family – warts, uterine cervical carcinoma  Herpes virus family – Burkitt’s and nasopharyngeal lymphoma  Hepdna virus family – liver carcinoma (hepatocellular)

Clinical Application Potential Diagnostic Uses o Screening for malignancy and cancer susceptibility via RFLP o Genetic counseling pre- or post-natally o Gene amplification as useful tumor marker o Tumor marker production from oncogene products o Identification of cancer-prone individuals Potential Therapeutic Applications o Anti-oncogene therapeutics – anti-idiotype monoclonal antibodies against oncogene growth factors and cell surface receptors o Anti-oncogene nucleic acid therapeutics o Cancer vaccines