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Chapter 13 : Under the Influence: from the Provirus Hypothesis to Multistep Carcinogenesis
A part of a first group at University of California at San Francisco (UCSF) worked on the early events in retrovirus replication that result in the establishment of a provirus. Another part worked on aspects of proviral gene expression, especially mechanisms, such as ribosomal frameshifting, that permit synthesis of the viral enzymes required for forming a provirus. Yet another portion of the group studied the oncogenic consequences of proviral integration, including insertional activation and the capture of host proto-oncogenes. All of these components, arrayed around a schematic drawing of a provirus, revealed the depth of commitment to Teminism. The idea that insertional activation of proto-oncogenes might constitute the first step in a cancerous process initiated by retroviruses lacking viral oncogenes took flight with the demonstration that avian leukosis viruses augment expression of the c-myc proto-oncogene by nearby integration of its provirus. These findings stimulated similar work with the mouse mammary tumor virus (MMTV), resulting in the discovery of the Wnt-1 gene, the first cloned member of a large gene family known to govern early developmental events in diverse organisms. In the studies the first group has moved beyond the study of MMTV proviruses as insertional mutagens to consider more broadly the multistep nature of mammary carcinogenesis in hopes of understanding the genetic and physiological events that produce premalignant lesions, primary cancers, and metastases in human beings as well as mice.