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Role of RNA structures in c-myc and c-fos gene regulations
M Piechaczyk1, J M Blanchard, A Bonnieu
1Laboratoire de Biologie Moléculaire, UA CNRS 1191, USTL, Montpellier, France.
Abstract:
Proto-oncogenes c-myc and c-fos are subjected to a complex set of controls operating both at the transcriptional and post-transcriptional levels. We report here that: (i) antisense transcription occurs at the murine c-myc locus. However, its biological significance remains to be established; (ii) transcription of both genes is regulated in various situations by a block to elongation of nascent RNA chains. In the case of c-myc, the blockade involves a RNA structure whose nature remains unknown; (iii) elements responsible for the high degree of instability of c-myc and c-fos mRNAs reside in their 3' non-coding regions. A U-rich region, reminiscent of that present in the granulocyte-monocyte colony-stimulating factor mRNA destabilizer, is likely to be involved in the rapid degradation of c-fos mRNA; (iv) exon 1 substitution by intron 1-derived sequences lessens or negates the effect of the 3' destabilizer in abnormal c-myc RNAs from Burkitt's lymphomas and mouse plasmacytomas.
Insights
This study reveals complex gene regulation of proto-oncogenes c-myc and c-fos. Key findings include antisense transcription, transcriptional blocks, and mRNA instability linked to 3' non-coding regions.
Area of Science:
- Molecular Biology
- Oncogenesis
- Gene Regulation
Background:
- Proto-oncogenes c-myc and c-fos play critical roles in cellular processes.
- Their expression is tightly controlled at multiple regulatory levels.
- Dysregulation of these genes is implicated in various cancers.
Purpose of the Study:
- To investigate the intricate transcriptional and post-transcriptional regulatory mechanisms of c-myc and c-fos.
- To elucidate the role of antisense transcription and RNA processing in gene expression.
- To identify elements contributing to mRNA stability and their implications in oncogenesis.
Main Methods:
- Analysis of antisense transcription at the murine c-myc locus.
- Investigation of transcriptional elongation blocks affecting c-myc and c-fos.
- Mapping of mRNA instability determinants to 3' non-coding regions.
- Assessment of exon-intron substitutions on mRNA stability in abnormal c-myc RNAs.
Main Results:
- Antisense transcription was detected at the murine c-myc locus, though its function is unclear.
- Both c-myc and c-fos transcription are regulated by elongation blocks, involving a specific RNA structure for c-myc.
- mRNA instability of c-myc and c-fos is primarily determined by their 3' non-coding regions.
- A U-rich region in the 3' non-coding region of c-fos mRNA is implicated in its rapid degradation.
- Substitution of exon 1 with intron 1 sequences reduced the destabilizing effect of the 3' region in abnormal c-myc RNAs.
Conclusions:
- Proto-oncogene regulation involves complex interplay between transcription and post-transcriptional control.
- 3' non-coding regions are critical determinants of c-myc and c-fos mRNA stability.
- Understanding these regulatory mechanisms offers potential therapeutic targets for cancers driven by c-myc and c-fos dysregulation.