Polyamine depletion up-regulates c-Myc expression, yet induces G(1) arrestand 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 OD C levels, whereas stationary phase cells and terminally differentiated cell s have low levels of both proteins. Therefore, we were surprised to find th at when F9 teratocarcinoma stem cells were blocked in the G(1) phase of the ir cell cycle and induced to differentiate by irreversible inhibition of th e ODC activity, the expression of c-Myc was up-regulated instead of being d own-regulated During the course of differentiation, the c-myc gene was cons titutively expressed, and c-Myc protein accumulated. In transfection experi ments, using ODC promoter-reporter gene fusion constructs, the accumulation of c-Myc protein, resulting from polyamine depletion, led to increased rep orter gene expression. This finding is consistent with the view that deplet ion of polyamines relieves the suppression that they exert on c-myc mRNA tr anslation, causing an accumulation of c-Myc protein, which in turn transact ivates 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 su ggest a new role for polyamines-as negative regulators of c-Myc expression. J. Cell. Biochem. 76:143-152, 1999. (C) 1999 Wiley-Liss, Inc.