HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 5, 3327-3339, January 30, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/5/3327    most recent M310872200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Lynch, M. Articles by Schmidt, E. V. Search for Related Content PubMed PubMed Citation Articles by Lynch, M. Articles by Schmidt, E. V. Social Bookmarking                      What's this?

Activated eIF4E-binding Protein Slows G₁ Progression and Blocks Transformation by c-myc without Inhibiting Cell Growth^*

Mary Lynch, Chris Fitzgerald, Kelly A. Johnston, Shanping Wang, and Emmett V. Schmidt¶

From the Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, and The Pediatric Service, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

Translation initiation is poised between global regulation of cell growth and specific regulation of cell division. The mRNA cap-binding protein (eIF4E) is a critical integrator of cell growth and division because it is rate-limiting for translation initiation and is also rate-limiting for G₁ progression. Translation initiation factor eIF4E is also oncogenic and a candidate target of c-myc. Recently, an activated inhibitory 4E-binding protein (4EBP) that blocks eIF4E was used to study its regulation of Drosophila growth. We adopted this approach in mammalian cells after identifying an autosensing mechanism that protects against increased levels of 4EBP1. Increased 4EBP1 induced a quantitative increase in the inactivated phosphorylated form of 4EBP1 in vitro and in vivo. To overcome this protective mechanism, we introduced alanine substitutions at four phosphorylation/inactivation sites in 4EBP1 to constitutively activate a 4EBPµ to block eIF4E. Overexpression of activated 4EBPµ inhibited cell proliferation and completely blocked transformation by both eIF4E and c-myc, although it did not block all tested oncogenes. Surprisingly, expression of the activated 4EBPµ increased cell size and protein content. Activated 4EBPµ blocked both cell proliferation and c-myc transformation by inhibiting G₁ progression and increasing apoptosis, without decreasing protein synthesis. Our results identify mammalian eIF4E as rate-limiting for cell cycle progression before it regulates cell growth. It further identifies G₁ control by translation initiation factors as an essential genetic target of c-myc that is necessary for its ability to transform cells.

Received for publication, October 2, 2003 , and in revised form, November 6, 2003.

^* This work was supported by NCI Grant RO1-CA63117 from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: The Pediatric Service, Massachusetts General Hospital and Harvard Medical School, Fruit St., Boston, MA 02114. Tel.: 617-726-5707; Fax: 617-726-5637; E-mail: Schmidt{at}helix.mgh.harvard.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				N. Kobayashi, R. J. Barnard, J. Said, J. Hong-Gonzalez, D. M. Corman, M. Ku, N. B. Doan, D. Gui, D. Elashoff, P. Cohen, et al. Effect of Low-Fat Diet on Development of Prostate Cancer and Akt Phosphorylation in the Hi-Myc Transgenic Mouse Model Cancer Res., April 15, 2008; 68(8): 3066 - 3073. [Abstract] [Full Text] [PDF]

				M. J. Ravitz, L. Chen, M. Lynch, and E. V. Schmidt c-myc Repression of TSC2 Contributes to Control of Translation Initiation and Myc-Induced Transformation Cancer Res., December 1, 2007; 67(23): 11209 - 11217. [Abstract] [Full Text] [PDF]

				P. Sangthong, J. Hughes, and J. E. G. McCarthy Distributed control for recruitment, scanning and subunit joining steps of translation initiation Nucleic Acids Res., June 28, 2007; 35(11): 3573 - 3580. [Abstract] [Full Text] [PDF]

				E. F. Petricoin III, V. Espina, R. P. Araujo, B. Midura, C. Yeung, X. Wan, G. S. Eichler, D. J. Johann Jr., S. Qualman, M. Tsokos, et al. Phosphoprotein Pathway Mapping: Akt/Mammalian Target of Rapamycin Activation Is Negatively Associated with Childhood Rhabdomyosarcoma Survival Cancer Res., April 1, 2007; 67(7): 3431 - 3440. [Abstract] [Full Text] [PDF]

				M. Lynch, L. Chen, M. J. Ravitz, S. Mehtani, K. Korenblat, M. J. Pazin, and E. V. Schmidt hnRNP K Binds a Core Polypyrimidine Element in the Eukaryotic Translation Initiation Factor 4E (eIF4E) Promoter, and Its Regulation of eIF4E Contributes to Neoplastic Transformation Mol. Cell. Biol., August 1, 2005; 25(15): 6436 - 6453. [Abstract] [Full Text] [PDF]

				A. G. Bader and P. K. Vogt Inhibition of Protein Synthesis by Y Box-Binding Protein 1 Blocks Oncogenic Cell Transformation Mol. Cell. Biol., March 15, 2005; 25(6): 2095 - 2106. [Abstract] [Full Text] [PDF]

				U. E. Knies-Bamforth, S. B. Fox, R. Poulsom, G. I. Evan, and A. L. Harris c-Myc Interacts with Hypoxia to Induce Angiogenesis In vivo by a Vascular Endothelial Growth Factor-Dependent Mechanism Cancer Res., September 15, 2004; 64(18): 6563 - 6570. [Abstract] [Full Text] [PDF]

				N. Hay and N. Sonenberg Upstream and downstream of mTOR Genes & Dev., August 15, 2004; 18(16): 1926 - 1945. [Abstract] [Full Text] [PDF]