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Nucleic Acids Research, 2000, Vol. 28, No. 11 2268-2275
© 2000 Oxford University Press

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

Annette Janz1,2, Cinzia Sevignani3, Karla Kenyon2, Cam V. Ngo3 and Andrei Thomas-Tikhonenko2,3,*

1Technische Universität Braunschweig, D-38023 Braunschweig, Germany, 2Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA and 3Department of Pathobiology, University of Pennsylvania, Philadelphia, PA 19104, USA

The Myc oncoprotein is implicated in transcriptional regulation of a variety 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, Myc is thought to induce changes in transcription initiation. We have previously shown that overexpression of Myc causes down-regulation of the thrombospondin-1 (tsp-1) gene, an important negative modulator of tumor angiogenesis. 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-1 promoter. However, the 2.7 kb DNA segment containing both this non-canonical E-box and an Inr-like sequence does not constitute a Myc-responsive element in a transient expression system. Furthermore, Myc does not significantly affect the rate of initiation or elongation of the tsp-1 mRNA. Thus, in this instance Myc does not act as a canonical transcription factor. Instead, as demonstrated by blocking de novo RNA synthesis, down-regulation of the tsp-1 gene by Myc occurs through increased mRNA turnover. To our knowledge, this is the first example of gene regulation by Myc that involves mRNA destabilization.

* To whom correspondence should be addressed at: Department of Pathobiology, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104-6051, USA. Tel: +1 215 573 5138; Fax: +1 215 898 0719; Email: andreit@vet.upenn.edu Present address: Annette Janz, GSF-Haematologikum, Institut für Klinische Molekularbiologie, D-81377 München, Germany


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