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Regulation and function of non-AUG-initiated proto-oncogenes
1Department of Cell Biology, Vanderbilt University, School of Medicine, Nashville, TN 37232-2175.
Abstract:
A small, yet growing, number of cellular eukaryotic mRNAs encoding important regulatory proteins, such as c-myc and other proto-oncogenes, initiate translation from a non-AUG codon, usually in addition to initiating at a downstream AUG. The efficiency of non-AUG initiation on these natural cellular mRNAs varies considerably and appears to be governed by several features, including the codon sequence, the context surrounding the codon and the secondary structure of the transcript. In addition to factors which control the overall efficiency of c-myc non-AUG initiation, the relative efficiency of the upstream non-AUG initiation compared with the AUG initiation changes during the growth of cells. As lymphoid and fibroblast cells approach high densities in culture there is a sustained 5-10-fold induction in the synthesis of the non-AUG-initiated c-Myc 1 protein to levels comparable to or greater than the AUG-initiated c-Myc 2 protein. This increased efficiency of c-myc non-AUG initiation, due to methionine depletion of the growth medium, suggests that the scanning preinitiation complex can be regulated to enhance the recognition of a suboptimal non-AUG codon. The significance of non-AUG initiation for the growth-regulatory genes is illustrated by the different localizations of the int-2, bFGF and hck non-AUG-initiated proteins, the disruption of the c-myc and lyl-1 non-AUG initiation in tumor-derived cell lines, and the distinct biological function of the non-AUG-initiated forms of bFGF.
Insights
Some genes initiate protein production using non-AUG codons, impacting cell growth regulation. This process, particularly for c-myc, is enhanced by methionine depletion, suggesting regulatory control over translation initiation.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- Eukaryotic messenger RNAs (mRNAs) can initiate translation from non-AUG codons, in addition to the canonical AUG start codon.
- This alternative translation initiation is observed for important regulatory proteins, including proto-oncogenes like c-myc.
- The efficiency of non-AUG initiation is influenced by codon sequence, surrounding context, and transcript secondary structure.
Purpose of the Study:
- To investigate the regulation of non-AUG translation initiation in cellular mRNAs.
- To explore how cellular conditions, such as cell density and nutrient availability, affect non-AUG initiation efficiency.
- To understand the biological significance of non-AUG initiation for growth-regulatory genes.
Main Methods:
- Analysis of natural cellular mRNAs encoding regulatory proteins.
- Investigating the impact of cell density and methionine depletion on protein synthesis.
- Comparing the efficiency of non-AUG versus AUG initiation under different cellular conditions.
Main Results:
- Non-AUG initiation efficiency varies for natural mRNAs and is influenced by transcript features.
- As cells reach high density, c-myc non-AUG initiation is significantly induced (5-10 fold), especially under methionine depletion.
- This induction leads to non-AUG-initiated c-Myc 1 protein levels comparable to or exceeding AUG-initiated c-Myc 2 protein.
Conclusions:
- The scanning preinitiation complex can be regulated to enhance recognition of suboptimal non-AUG codons.
- Methionine availability is a key factor influencing the efficiency of non-AUG initiation for c-myc.
- Non-AUG initiation plays a significant role in the function and localization of growth-regulatory proteins like int-2, bFGF, and hck.