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Functional analysis of the AUG- and CUG-initiated forms of the c-Myc protein.

Blackwood, E M and Lugo, T G and Kretzner, L and King, M W and Street, A J and Witte, O N and Eisenman, R N (1994) Functional analysis of the AUG- and CUG-initiated forms of the c-Myc protein. Molecular biology of the cell, 5 (5). pp. 597-609. ISSN 1059-1524

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Article URL: http://www.molbiolcell.org/cgi/content/abstract/5/...

Abstract

Activation of the c-myc proto-oncogene by chromosomal translocation or proviral insertion frequently results in the separation of the c-myc coding region from its normal regulatory elements. Such rearrangements are often accompanied by loss or mutation of c-myc exon 1 sequences. These genetic alterations do not affect synthesis of the major c-myc protein, p64, which is initiated from the first AUG codon in exon 2. However they can result in mutation or loss of the CUG codon located in exon 1 that normally serves as an alternative translational initiation codon for synthesis of an N-terminally extended form of c-Myc (p67). It has been hypothesized that p67 is a functionally distinct form of c-Myc whose specific loss during c-myc rearrangements confers a selective growth advantage. Here we describe experiments designed to test the functional properties of the two c-Myc protein forms. We introduced mutations within the translational initiation codons of a normal human c-myc cDNA that alter the pattern of Myc protein synthesis (p64 vs. p67). The functions of each of these proteins were experimentally addressed using co-transformation and transcriptional activation assays. Both the p64 and p67 c-Myc proteins were independently able to collaborate with bcr-abl in the transformation of Rat-1 fibroblasts. In addition, both the exon 1- and exon 2-initiated forms of the c-Myc protein stimulated transcription of a Myc/Max-responsive reporter construct to a similar level. Given the apparent absence of functional differences between p64 and p67, we conclude that the basis for c-Myc oncogenic activation lies primarily in the overall deregulation of its expression and not in alterations in the protein. The existence of the CUG translational initiator may reflect a mechanism for the continued synthesis of c-Myc protein under conditions where AUG initiation is inhibited.

Item Type: Article
Additional Information: This article is freely available in PubMed Central and at the journal's website.
PubMed ID: 7919540
PMCID: PMC301071
Grant Numbers: T32 CA-09437, R01 CA-20525, R35CA-53867, lT32GM08243
Keywords or MeSH Headings: Amino Acid Sequence; Animals; Base Sequence; Cell Line; Codon, Initiator/genetics; DNA, Complementary/genetics; Gene Expression Regulation; Genes, Reporter; Genetic Vectors; Humans; Mice; Molecular Sequence Data; Mutagenesis, Site-Directed; Peptide Chain Initiation, Translational/genetics; Protein Biosynthesis; Proto-Oncogene Proteins c-myc/biosynthesis/genetics; Rats; Retroviridae/genetics; Transformation, Genetic;
Subjects: Cellular and Organismal Processes > Genetic processes > Mutation
Cellular and Organismal Processes > Genetic processes > Translation
Molecules > Genes > Oncogenes
Depositing User: Library Staff
Date Deposited: 26 Nov 2008 22:55
Last Modified: 21 May 2010 23:10
URI: http://authors.fhcrc.org/id/eprint/150

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