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 repressing a repertoire of genes involved in cellular proliferation, metabolism, and apoptosis. Increasing evidence suggests that the repressor function of c-Myc is critical for transformation. Therefore, identifying and characterizing 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 caveolin-1 expression. In this well-established inducible system, treatment with estrogen like molecules, such as tamoxifen, leads to activation of Myc, but in a tightly controlled fashion. Using this approach, we show that Myc activation induces the repression of caveolin-1 expression at the transcriptional level. We also provide two independent lines of evidence suggesting that caveolin-1 is a direct target of Myc: (i) the effect of Myc activation on caveolin-1 expression is independent of new protein synthesis, as revealed through the use of cycloheximide; and (ii) Myc-mediated repression of the caveolin-1 promoter is dependent on an intact INR sequence. Moreover, we show that expression of caveolin-1, via an adenoviral vector approach, can suppress cell transformation that is mediated by Myc activation. In support of these observations, treatment with an adenoviral vector harboring anti-sense caveolin-1 specifically potentiates transformation induced by Myc activation. Taken together, our results indicate that caveolin-1 is a direct target of Myc repression, and they also provide evidence for an additional mechanism by which Myc repression can elicit a malignant phenotype.
Department of Molecular Pharmacology, and Albert Einstein Cancer Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
D S
DS
Park
B
B
Razani
A
A
Lasorella
N
N
Schreiber-Agus
R G
RG
Pestell
A
A
Iavarone
M P
MP
Lisanti
D016475:3T3 Cells; D020121:5' Untranslated Regions / Q000037:antagonists & inhibitors / Q000235:genetics; D000818:Animals; D051242:Caveolin 1; D022461:Caveolins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics*; D051379:Mice; D010641:Phenotype; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011960:Receptors, Estrogen / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection
D020121:5' Untranslated Regions; C495541:Cav1 protein, mouse; D051242:Caveolin 1; D022461:Caveolins; D020033:Protein Isoforms; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D012097:Repressor Proteins