Polyamine depletion up-regulates c-Myc expression, yet induces G(1) arrest and terminal differentiation of F9 teratocarcinoma stem cells.
The ornithine decarboxylase (ODC) gene is a transcriptional target of c-Myc. Exponentially growing cells usually exhibit high c-Myc levels and high ODC levels, whereas stationary phase cells and terminally differentiated cells have low levels of both proteins. Therefore, we were surprised to find that when F9 teratocarcinoma stem cells were blocked in the G(1) phase of their cell cycle and induced to differentiate by irreversible inhibition of the ODC activity, the expression of c-Myc was up-regulated instead of being down-regulated. During the course of differentiation, the c-myc gene was constitutively expressed, and c-Myc protein accumulated. In transfection experiments, using ODC promoter-reporter gene fusion constructs, the accumulation of c-Myc protein, resulting from polyamine depletion, led to increased reporter gene expression. This finding is consistent with the view that depletion of polyamines relieves the suppression that they exert on c-myc mRNA translation, causing an accumulation of c-Myc protein, which in turn transactivates its target gene, the bona fide ODC gene. Thus, the accumulation of an active c-Myc protein does not preclude differentiative events, nor does it override the growth arrest caused by polyamine depletion. These results suggest a new role for polyamines-as negative regulators of c-Myc expression.
Frostesjö
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Department of Cellular and Developmental Biology, Umeå University, S-901 87 Umeå, Sweden.
Heby
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O
D016475:3T3 Cells; D000818:Animals; D015317:Biogenic Polyamines / Q000378:metabolism*; D002454:Cell Differentiation; D016193:G1 Phase; D051379:Mice; D014176:Protein Biosynthesis; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D013234:Stem Cells / Q000473:pathology; D018243:Teratocarcinoma / Q000235:genetics / Q000473:pathology*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D015317:Biogenic Polyamines; D016271:Proto-Oncogene Proteins c-myc