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13.5: Oncogenes

The control of cell division involves many different genes. Some of these genes act as signaling molecules to activate normal progression through the cell cycle. One of the pre-requisites for cancer occurs when one or more of these activators of cell division become mutated.

The mutation may involve a change in the coding sequence of the protein, so that it is more active than normal, or a change in the regulation of its expression, so that it is produced at higher levels than normal, or persists in the cell longer than normal. Genes that are a part of the normal regulation of cell division, but which after mutation contribute to cancer, are called proto-oncogenes. Once a proto-oncogene has been abnormally activated by mutation, it is called an oncogene. More than 100 genes have been defined as proto-oncogenes. These include genes at almost every step of the signaling pathways that normally induce cell to divide, including growth factors, receptors, signal transducers, and transcription factors.  

Figure 13.6: HRas structure PDB 121p, ribbon showing strands in purple, helices in aqua, loops in gray. Also shown are the bound GTP analog and magnesium ion. (CC-BY-SA ElaineMeng)

ras is an example of a proto-oncogene. ras acts as a switch within signal transduction pathways, including the regulation of cell division. When a receptor protein receives a signal for cell division, the receptor activates ras, which in turn activates other signaling components, ultimately leading to activation of genes involved in cell division. Certain mutations of the ras sequence causes it to be in a permanently active form, which can lead to constitutive activation of the cell cycle. This mutation is dominant as are most oncogenes. An example of the role of ras in relaying a signal for cell division in the EGF pathway is shown in Figure 13.7.

Figure 13.7: Simplified representation of the epidermal growth factor (EGF) signaling pathway. In the panel on the left, the components are shown in their inactive forms, prior to stimulation of the pathway. The components include the soluble ligand, EGF, its receptor (EGFR, a tyrosine kinase), ras (a G protein), several kinases (RAF, MEK, MAPK), and a transcription factor (TF). In the right panel, the activate pathway is shown. Binding of the ligand to its receptor leads to autophosphorylation of the receptor. Through a series of proteins not shown here, the phosphorpylated simulates conversion of ras to its active, GTP-bound form. The activated ras then stimulates phosphorylation of a series of kinases, which ultimately activate transcription factors and the expression of genes required for cell proliferation. (Original-Deyholos-CC:AN)