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Oncogenes and Receptor Functions
Page 888 brane receptor, which appears to be the extracellular domain of guanylate cyclase. The cGMP produced activates protein kinase G, which further phosphorylates cellular proteins to express many of the actions of this pathway. More needs to be learned about protein kinase G. Using analogs of ANF it has been shown that the majority of receptors expressed in the kidney are biologically silent, since they fail to elicit a physiological response. This new class of receptors may serve as specific peripheral storage–clearance binding sites and as such act as a hormonal buffer system to modulate plasma levels of ANF. 20.13— Oncogenes and Receptor Functions Oncogenes are genes that are expressed by cancerous transformed cells. A cancer cell may express few or many oncogenes that dictate the aberrant uncontrolled behavior of the cell. There are three mechanisms by which oncogenes allow a cell to escape dependence on exogenous growth factors; these are presented in Figure 20.46. Some oncogenes are genes for parts of receptors, most often related to growth factor hormone receptors, which can function in the absence of the hormonal ligand. Thus an oncogene may represent a truncated gene where the ligandbinding domain is missing. This would result in production of the receptor protein, insertion into the cell membrane, and continuous constitutive function in the absence or presence of ligand (Figure 20.46b,c). In this situation the second messengers would be produced constitutively at a high rate, instead of being regulated by ligand, and the result would be uncontrolled growth of the cell. Some oncogenes may have tyrosine protein kinase activity and therefore function like tyrosine kinase normally related to certain cell membrane receptors. Other oncogenes relate to thyroid and steroid hormone receptors (see Chapter 21) while still others are DNAbinding proteins, some of which may be transactivating factors or related to such factors. Oncogene encoded proteins that bind to DNA may be identical with or related to transactivating factors. The oncogene Jun, for example, is a component of activator protein 1 (AP1), a transactivating factor that regulates transcription. Table 20.9 reviews some of the oncogenes, or cancercausing genes, together with the functions of their protooncogenes (normal proliferation gene). Figure 20.46 Mechanisms by which oncogenes can allow a cell to escape dependence on exogenous growth factors. (a) By autocrine mechanism, where the cytosolic oncogene indirectly stimulates expression of growth factor gene and oversecretion of growth factors, which then overstimulates receptors on same cell; (b) by receptor alteration so that receptor is ''permanently turned on" without a requirement for growth factor binding; and (c) by transducer alteration, where the intermediate between the receptor and its resultant activity, that is, the GTPstimulatory protein, is permanently activated, uncoupling the normal requirement of ligand–receptor binding. Redrawn from Weinberg, R. A. The action of oncogenes in the cytoplasm and nucleus. Science 230:770, 1985. Page 889 TABLE 20.9 Known Oncogenes, Their Products and Functionsa Name of Oncogene Retrovirus Oncogenic Protein VirusInduced Tumor src Chicken sarcoma Chicken sarcoma yes Chicken sarcoma fgr Cat sarcoma abl Mouse leukemia Human leukemia fps Chicken sarcoma fes Cat sarcoma ros Cellular Location Protooncogene Function Plasma membrane Tyrosinespecific protein kinase Plasma membrane (?) (?) Plasma membrane Tyrosinespecific protein kinase Cytoplasm (plasma membrane?) Sarcoma Cytoplasm (cytoskeleton?) Tyrosinespecific protein kinase Chicken sarcoma (?) erbB Chicken leukemia Erythroleukemia, fibrosarcoma Plasma and cytoplasmic membranes EGF receptor's cytoplasmic tyrosinespecific protein kinase domain fms Cat sarcoma Sarcoma Plasma and cytoplasmic membranes Tyrosinespecific protein kinase; macrophage colonystimulating factor receptor mil Chicken carcinoma Cytoplasm (?) raf Mouse sarcoma Sarcoma Cytoplasm Protein kinase (serine/threonine) activated by Ras mos Mouse sarcoma Mouse leukemia Cytoplasm (?) sis Monkey sarcoma Monkey sarcoma Secreted PDGFlike growth factor, bchain Haras Rat sarcoma Human carcinoma, rat carcinoma Plasma membrane GTPbinding protein Kiras Rat sarcoma Human carcinoma, leukemia, and sarcoma Plasma membrane GTPbinding protein Nras — Human leukemia and carcinoma Plasma membrane myc Chicken leukemia Sarcoma, myelocytoma, and carcinoma Nucleus DNAbinding related to cell proliferation; transcriptional control myb Chicken leukemia Human leukemia Nucleus (?) Blym — Chicken lymphoma, human lymphoma Nucleus (?) (?) ski Chicken sarcoma Nucleus (?) (?) rel Turkey leukemia Reticuloendotheliosis (?) (?) erbA Chicken leukemia (?) Thyroid hormone receptor (cerbA a1); related to steroid hormone receptors, retinoic acid receptor, and vitamin D3 receptor ets Chicken leukemia (?) DNA binding elk (etslike) DNAbinding protein jun Osteosarcoma Products associate to form AP1 gene transcription factor fos Fibrosarcoma Products associate to form AP1 gene transcription factor Source: Adapted from Hunter, T. The proteins of oncogenes. Sci. Am. 251:70, 1984. a The second column gives the source from which each viral oncogene was first isolated and the cancer induced by the oncogene. Some names, such as fps and fes, may be equivalent genes in birds and mammals. The third column lists human and animal tumors caused by agents other than viruses in which the ras oncogene or an inappropriately expressed protooncogene has been identified.