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Mouse c-mos oncogene activation is prevented by upstream sequences
Abstract:
Although the molecularly cloned mouse c-mos oncogene locus can be efficiently activated by insertion of a retroviral long terminal repeat (LTR) 5' to its coding region, only low-frequency transformation occurs with the LTR element inserted 3' to this region. Analysis of several of the latter transformed cell lines suggested that loss of 2 kilobases (kb) of normal mouse DNA sequences preceding c-mos was required for oncogene activation. The determination of the transforming potential of deletion mutants containing only portions of this region followed by analysis of their nucleotide sequences identified a region termed upstream mouse sequence (UMS) as a cis-acting locus that prevents c-mos activation by a 3' LTR. The UMS region is approximately 1 kb in length and is located 0.8-1.8 kb upstream from the first ATG in the open reading frame of c-mos. Insertion of UMS 5' to the v-mos coding region also prevents 3' LTR enhancement of its transforming activity, but this inhibition is position dependent and functions only when inserted between v-mos and its putative promoter. The results presented here suggest that UMS may function to regulate c-mos proto-oncogene expression and may explain the lack of detectable c-mos transcripts in normal mouse cells.
Insights
A newly identified upstream mouse sequence (UMS) region prevents the activation of the c-mos oncogene by a 3' retroviral long terminal repeat (LTR). This finding explains the low transformation frequency and lack of c-mos transcripts in normal cells.
Area of Science:
- Molecular biology
- Oncogene research
- Gene regulation
Background:
- The mouse c-mos oncogene can be activated by retroviral long terminal repeat (LTR) insertion.
- Activation is efficient when the LTR is 5' to the coding region, but inefficient when 3'.
Purpose of the Study:
- To identify the DNA sequences responsible for the differential activation of the c-mos oncogene by 3' LTR insertion.
- To elucidate the mechanism by which these sequences regulate c-mos expression.
Main Methods:
- Analysis of transformed cell lines with deletions in sequences preceding c-mos.
- Determination of transforming potential of deletion mutants.
- Nucleotide sequence analysis of identified regions.
- Functional assays involving insertion of identified regions 5' to the v-mos coding region.
Main Results:
- A 1 kb region, termed upstream mouse sequence (UMS), located 0.8-1.8 kb upstream of the c-mos coding region, was identified.
- UMS acts as a cis-acting locus preventing c-mos activation by a 3' LTR.
- UMS inhibits 3' LTR enhancement of v-mos transforming activity in a position-dependent manner.
Conclusions:
- UMS functions to regulate c-mos proto-oncogene expression.
- The UMS region likely explains the absence of detectable c-mos transcripts in normal mouse cells.