Evidence that Myc isoforms transcriptionally repress caveolin-1 gene expression via an INR-dependent mechanism

The c-Myc oncoprotein contributes to oncogenesis by activating and repressi ng a repertoire of genes involved in cellular proliferation, metabolism, an d apoptosis. Increasing evidence suggests that the repressor function of c- Myc is critical for transformation. Therefore, identifying and characterizi ng Myc-repressed genes is imperative to understanding the mechanisms of Myc -induced tumorigenesis, Here, we employ NIH 3T3 cell lines harboring c-Myc- ER or N-Myc-ER to dissect the relationship between Myc activation and caveo lin-l expression. In this well-established inducible system, treatment with estrogen like molecules, such as tamoxifen, leads to activation of Myc, bu t in a tightly controlled fashion. Using this approach, we show that Myc ac tivation induces the repression of caveolin-l expression at the transcripti onal level. We also provide two independent lines of evidence suggesting th at caveolin-l is a direct target of Myc: (i) the effect of Myc activation o n caveolin-l expression is independent of new protein synthesis, as reveale d through the use of cycloheximide; and (ii) Myc-mediated repression of the caveolin-l promoter is dependent on an intact INR sequence, Moreover, we s how that expression of caveolin-l, via an adenoviral vector approach, can s uppress cell transformation that is mediated by Myc activation. In support of these observations, treatment with an adenoviral vector harboring anti-s ense caveolin-l specifically potentiates transformation induced by Myc acti vation. Taken together, our results indicate that caveolin-l is a direct ta rget of Myc repression, and they also provide evidence for an additional me chanism by which Myc repression can elicit a malignant phenotype.