Activation of the Myc oncoprotein leads to increased turnover of thrombospondin-1 mRNA

The Myc oncoprotein is implicated in transcriptional regulation of a variet y of genes pertaining to cell cycle and neoplastic transformation. Examples of both positive and negative regulation have been reported that involve E -box and initiator (Inr) promoter elements, respectively. In both cases, My c is thought to induce changes in transcription initiation. We have previou sly shown that overexpression of Myc causes down-regulation of the thrombos pondin-l (tsp-1) gene, an important negative modulator of tumor angiogenesi s. In this study, we demonstrate that Myc in combination with Max can bind, albeit with low affinity, to an E-box-like element in the tsp-l promoter. However, the 2.7 kb DNA segment containing both this non-canonical E-box an d an Inr-like sequence does not constitute a Myc-responsive element in a tr ansient expression system. Furthermore, Myc does not significantly affect t he rate of initiation or elongation of the tsp-l mRNA. Thus, in this instan ce Myc does not act as a canonical transcription factor. Instead, as demons trated by blocking de novo RNA synthesis, down-regulation of the tsp-l gene by Myc occurs through increased mRNA turnover, To our knowledge, this is t he first example of gene regulation by Myc that involves mRNA destabilizati on.