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Journal of Virology, September 1999, p. 7599-7606, Vol. 73, No. 9
Department of Molecular Genetics, Albert
Einstein College of Medicine, Bronx, New York
10461,1 and Tulane University School
of Medicine, New Orleans, Louisiana 701122
Received 5 February 1999/Accepted 25 May 1999
The retrovirus SL3 induces T-cell lymphomas in mice. The
transcriptional enhancer in the long terminal repeat (LTR) of SL3 contains two 72-bp repeats. Each repeat contains a binding site for the
transcription factor CBF (also called AML1). The CBF binding sites are called core elements. SAA is a mutant that is
identical to SL3 except for the presence of a single-base-pair
substitution in each of the two core elements. This mutation
significantly attenuates viral lymphomagenicity. Most lymphomas that
occur in SAA-infected mice contain proviruses with reversions or
second-site suppressor mutations within the core element. We examined
the selective pressures that might account for the
predominance of the reversions and suppressor mutations in tumor
proviruses by analyzing when proviruses with altered core sequences
became abundant during the course of lymphomagenesis. Altered core
sequences were easily detected in thymus DNAs by 4 to 6 weeks after SAA
infection of mice, well before lymphomas were grossly evident. This
result is consistent with the hypothesis that viruses with the core
sequence alterations emerged because they replicated more effectively
in mice than SAA. The number of 72-bp tandem, repeats in the viral LTR
was found to vary, presumably as a consequence of reverse transcriptase
slippage during polymerization. Proviruses with two repeats
predominated in the thymuses of SAA- and SL3-infected mice before
lymphomas developed, although LTRs with one or three repeats were also
present. This suggested that two was the optimal number of 72-bp
repeats for viral replication. However, in lymphomas, proviruses with three or four repeats usually predominated. This suggested that a late step in the process of lymphomagenesis led to the
abundance of proviruses with additional repeats. We hypothesize that proviruses with additional 72-bp repeats endowed the cells containing them with a selective growth advantage.
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Selection of Reversions and Suppressors of a
Mutation in the CBF Binding Site of a Lymphomagenic
Retrovirus
*
Corresponding author. Mailing address: Department of
Molecular Genetics, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Phone: (718) 430-3715. Fax: (718) 430-8778. E-mail: lenz{at}aecom.yu.edu.
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