Oncogenes

> The first group of oncogenes to have been discovered form parts of the genomes of acutely transforming retroviruses, which cause hematological or soft tissue cancers in their avian or mammalian hosts. They act in a dominant manner and confer altered growth properties and morphology on specific target cells in mesenchymal tissues or the hematopoetic system.

> A second group of oncogenes consists of host proto-oncogenes that become activated when the insertion of slowly transforming retroviruses disrupts their regulation.

> Retroviral insertion is only one of several mechanisms that can activate cellular proto-oncogenes to dominantly acting oncogenes. Other mechanisms include chromosomal translocation, gene amplification and point mutations. These mechanisms alter the regulation and/or function of cellular genes, which are thereby activated from proto-oncogenes towards oncogenes. As a consequence of these alterations, their protein products become overexpressed or deregulated and/or become overactive or mislocalized in the cell.

^ The oncogenes of acutely transforming retroviruses are in fact also derived from host genes, and have become deregulated and overactive by expression from the retroviral long terminal repeat and by mutations. Several genes such as NRAS, KRAS, ERBB1, and MYC orthologous to viral oncogenes have turned out to be overexpressed or mutated in human cancers. The cellular orthologs of other retroviral oncogenes are more subtly involved in human cancers.

> Many cellular proto-oncogenes regulate cell proliferation, differentiation and survival also in their normal state. Some act as extracellular growth factors, some as their receptors and some as juxtamembrane adaptors or transducers in signaling cascades emanating from growth factor receptors or other membrane receptors. A large class of proto-oncogene products are protein kinases. They include growth factor receptors with a crucial tyrosine kinase activity. Other kinases are located in the cytoplasm. A further large group of protooncogenes consists of transcription factors acting in the nucleus. So, oncogenes can be categorized according to their cellular localization and/or their biochemical function. Indeed, a surprisingly large number of proto-oncogenes functions within or interacts with a single signaling network. At its core is the mitogenic 'MAP kinase' cascade which links growth factor signaling to transcription in the nucleus and to the cell cycle, but also influences protein synthesis and the cytoskeleton.

^ Growth factor signaling and the MAPK cascade are tightly regulated in normal cells by feedback regulation and by short half-lifes of activated states. Oncogenic mutations make oncogene proteins independent of input signals, disrupt feedback regulation or prolong their active state.

> There are very few cases in which a single oncogene is sufficient to fully transform a cell towards malignancy. Rather, a single oncogene confers some aspects of the malignant phenotype and cooperates with others or with defects in tumor suppressors for complete transformation. This relationship is illustrated in cellular assay systems such as rat embryo fibroblasts, in which two different types of oncogenes are required for transformation. ^ Human cancers accumulate many genetic and epigenetic alterations during their progression. In a typical cancer many genes are overexpressed and many gene products are overactive. A fraction of these may indeed be necessary for the survival and sustained growth of the cancer. So, they might be regarded as oncogenes as well. A more strictly defined oncogene exhibits these same properties, but its overexpression or overactivity is caused by substantial changes in the gene, i.e. mutations or amplifications.

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