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J. Biol. Chem., Vol. 281, Issue 2, 695-704, January 13, 2006

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Control of MYEOV Protein Synthesis by Upstream Open Reading Frames^*

From the Institute of Human Genetics, University of Heidelberg, Im Neuenheimer Feld 366, D-69120 Heidelberg, Germany

The myeov gene has been isolated by the tumorigenicity assay and is localized at chromosome 11q13, a frequent site for chromosomal rearrangements in various carcinomas and B-cell neoplasms. In addition, myeov is coamplified with cyclin D1 and overexpressed in carcinomas of various organs. The mechanisms of myeov regulation remain enigmatic. The 5'-untranslated region (5'-UTR) of the myeov gene is long, encompasses several upstream AUGs, and is predicted to fold in a strong secondary structure, suggesting that its translation might be regulated by an internal ribosomal entry site. Here we show that initial experiments using monocistronic and dicistronic reporter constructs supported this assumption. However, the application of in vitro transcription/translation assays, Northern blot analysis, and promoterless dicistronic constructs revealed promoter activity of the myeov 5'-UTR. DNA transfection of dicistronic DNA constructs, normal and mutated forms of myeov cDNA fragments cloned in a eukaryotic expression vector, and direct RNA transfection analysis revealed that upstream AUG triplets in the 5'-UTR of the myeov transcript abrogate translation. Alternative splicing mechanisms in specific cell types and/or developmental stage may evade this translation control. Control experiments suggest that the 5'-UTR from encephalomyocarditis virus, when inserted at the midpoint of a dicistronic vector, is also able to function as a cryptic promoter.

Received for publication, October 21, 2005 , and in revised form, November 7, 2005.

^* This work was supported by Dr. Mildred Scheel Stiftung für Krebsforschung Grant 10-1855-Ja2 (to J. W. G. J.). 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.

¹ Present address: The Michael Smith Bldg., Faculty of Life Sciences, University of Manchester, Oxford Rd., Manchester M13 9PT, United Kingdom.

² To whom correspondence should be addressed: Institute of Human Genetics, Im Neuenheimer Feld 366, D-69120 Heidelberg, Germany. Tel.: 49-6221-565062 or 49-6221-565064; Fax: 49-6221-565155; E-mail: hans_janssen{at}med.uniheidelberg.de.

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				M. S. Sachs and A. P. Geballe Downstream control of upstream open reading frames Genes & Dev., April 15, 2006; 20(8): 915 - 921. [Full Text] [PDF]