Liver hyperplasia after tamoxifen induction of Myc in a transgenic medaka model

Abstract

Summary Myc is a global transcriptional regulator and one of the most frequently overexpressed oncogenes in human tumors. It is well established that activation of Myc leads to enhanced cell proliferation but can also lead to increased apoptosis. The use of animal models expressing deregulated levels of C-myc has helped elucidate its function in normal cells and also give insights on how Myc initiates and maintains tumorigenesis. Analyses of the medaka (Oryzias latipes) genome uncovered the unexpected presence of two C-myc gene copies in this teleost species. Comparison of these C-myc versions to other vertebrate species, revealed that one gene, c-myc17, differs by the loss of some conserved regulatory protein motifs present in all other known c-myc genes. To investigate how such differences might affect the basic biological functions of Myc, we generated a tamoxifen inducible in vivo model utilizing a natural, fish-specific myc gene. Using this model we show that when activated, C-myc17 leads to increased proliferation and to apoptosis in a dose dependent manner, similar to human Myc. We have also shown that long-term C-myc17 activation triggers liver hyperplasia in adult fish, allowing this newly established transgenic medaka model to be used to study the transition from hyperplasia to liver cancer and to identify of Myc-induced tumorgenesis modifiers.