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Negative regulation of c-myc transcription involves myc family proteins
J L Cleveland1, M Huleihel, P Bressler
1Laboratory of Viral Carcinogenesis, National Cancer Institute, FCRF, Frederick, Maryland 21701.
Abstract:
Expression of the c-myc gene is suppressed in NIH 3T3 mouse fibroblast cells infected with recombinant retroviruses expressing high levels of v-myc (10-fold greater than those of c-myc). Suppression of steady state levels of c-myc mRNA occurred at least in part at the level of transcription from c-myc promoters P1 and P2, and involved v-myc protein since cells infected with constructs containing frameshifts and deletions in v-myc had normal levels of c-myc mRNA and protein. Suppression of c-myc expression was also observed in fibroblasts transfected with a N-myc expression vector and in fibroblasts infected with a c-myc retrovirus. These findings establish that v-myc protein is involved either directly or indirectly in a regulatory circuit which represses c-myc proto-oncogene transcription. Feedback regulation of c-myc transcription may be relevant in establishing the lineage specific expression of myc family proto-oncogenes. Reduced steady state levels of c-myc mRNA were also observed in NIH 3T3 cells infected with 12S and 13S EIA recombinant retroviruses suggesting that the exogenous oncogene of adenovirus, EIA, can alleviate the requirement of myc for cell growth and may also share transcriptional target genes.
Insights
High levels of v-myc oncogene expression suppress c-myc gene transcription in mouse cells. This feedback regulation by v-myc protein impacts proto-oncogene expression and may influence cell growth.
Area of Science:
- Molecular Biology
- Oncology
- Gene Regulation
Background:
- The c-myc gene is a crucial proto-oncogene involved in cell proliferation.
- Understanding the regulation of myc family genes is vital for comprehending cancer development.
Purpose of the Study:
- To investigate the regulatory relationship between v-myc and c-myc expression.
- To determine the role of v-myc protein in controlling c-myc transcription.
Main Methods:
- Utilized recombinant retroviruses to express high levels of v-myc in NIH 3T3 mouse fibroblast cells.
- Analyzed c-myc mRNA and protein levels via transcription assays.
- Examined N-myc and c-myc retroviral infections and adenovirus EIA effects.
Main Results:
- High v-myc expression significantly suppressed c-myc mRNA and protein levels.
- Suppression occurred at the transcriptional level, involving c-myc promoters P1 and P2.
- v-myc protein was essential for this repression; mutations abolished the effect.
- Similar suppression was seen with N-myc and c-myc retroviruses.
- Adenovirus EIA also reduced c-myc mRNA, suggesting shared regulatory pathways.
Conclusions:
- v-myc protein actively participates in a regulatory circuit that represses c-myc proto-oncogene transcription.
- This feedback mechanism may be important for lineage-specific expression of myc family genes.
- Adenovirus EIA may influence cell growth by affecting myc-dependent pathways.