This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ravitz, M. J. Articles by Schmidt, E. V. Search for Related Content PubMed PubMed Citation Articles by Ravitz, M. J. Articles by Schmidt, E. V.

c-myc Repression of TSC2 Contributes to Control of Translation Initiation and Myc-Induced Transformation

¹ Cancer Research Center at Massachusetts General Hospital and Harvard Medical School and ² Department of Pediatrics, Harvard Medical School, Massachusetts General Hospital for Children, Boston, Massachusetts

Requests for reprints: Emmett V. Schmidt, MGH Cancer Research Center, MGH Cancer Center-Harvard University, 55 Fruit Street, GRJ 904, Boston, MA 02114. Phone: 617-726-5707; Fax: 617-726-8623; E-mail: Schmidt{at}helix.mgh.harvard.edu.

The c-myc oncogene plays a key role in cellular growth control, and translation initiation factors are among the transcriptional targets of Myc. Here, we describe a defect in translation initiation control in myc-null cells due to alterations in the mammalian target of rapamycin (mTOR) pathway. Myc loss increased sensitivity to dominant inhibition of eukaryotic translation initiation factor 4E function. Polysomal profiles of myc^–/– cells revealed decreased translation initiation rates, which were accompanied by decreased 40S/60S ribosomal subunit ratios. Because the 40S small ribosomal subunit contains the key regulatory ribosomal protein S6 (rpS6), we considered that myc loss might affect expression of components of the mTOR signaling pathway that regulate rpS6 function. Among mTOR signaling components, Myc directly affected transcription of tuberous sclerosis 2 (TSC2), as shown by quantitative mRNA analysis and by Myc binding to its promoter in chromatin immunoprecipitation assays. Importantly, Myc acted as a strong and direct repressor for TSC2 expression because its loss increased TSC2 mRNA in myc-null and in HL60 shRNA experiments, activation of a mycER construct in myc^–/– cells suppressed TSC2 induction in a myc box II–dependent manner, and mycER activation recruited Myc to the TSC2 promoter. The biological significance of the effect of Myc on TSC2 expression was shown by markedly reduced TSC2 mRNA levels in myc-transformed cells, stimulation of S6 kinase activity in myc-null cells by TSC2 siRNA, and decreased Myc-induced soft agar colony formation following retroviral transduction of TSC2. Together, these findings show that regulation of TSC2 can contribute to the effects of Myc on cell proliferation and neoplastic growth. [Cancer Res 2007;67(23):11209–17]

This article has been cited by other articles:

				C.-J. Lin, A. Malina, and J. Pelletier c-Myc and eIF4F Constitute a Feedforward Loop That Regulates Cell Growth: Implications for Anticancer Therapy Cancer Res., October 1, 2009; 69(19): 7491 - 7494. [Abstract] [Full Text] [PDF]

				J. Singh and M. Tyers A Rab escort protein integrates the secretion system with TOR signaling and ribosome biogenesis Genes & Dev., August 15, 2009; 23(16): 1944 - 1958. [Abstract] [Full Text] [PDF]