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Retroviral Scanning: Mapping MLV Integration Sites to Define Cell-specific Regulatory Regions
Published on: May 28, 2017
The twist gene is a common target of retroviral integration and transcriptional deregulation in experimental
Petr Pajer1, Vladimír Pecenka, Vít Karafiát
1Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague.
Abstract:
The genes involved in the transformation of kidney blastema cells were searched for in avian nephroblastomas induced by the MAV2 retrovirus. The twist gene was identified as a common site of provirus integration in tumor cells. Twist was rearranged by the MAV2 provirus in three out of 76 independent nephroblastoma samples. The MAV2 integration sites were localized within 40 nucleotides of the twist 5'UTR region, right upstream from the ATG initiation codon. The integrated proviruses were deleted at their 5'ends. As a consequence, twist transcription became controlled by the retroviral 3'LTR promoter and was strongly upregulated, more than 200 times. In addition, 2-100 times elevated twist transcription was also detected in the majority of other nephroblastoma samples not containing MAV2 in the twist locus. We propose that chicken nephroblastoma originates from a single blastemic cell in which the MAV retrovirus, through its integration, has deregulated specific combinations of genes controlling proliferation and differentiation. The activation of the twist gene expression appears to contribute to tumorigenesis, as there is an in vivo positive selection of tumor cell clones containing the twist gene hyperactivated by MAV2 sequences inserted within the twist promoter.
Insights
The MAV2 retrovirus activates the twist gene in avian nephroblastomas, promoting cancer cell growth. This gene activation, through retroviral integration, is a key factor in the development of these kidney tumors.
Area of Science:
- Oncology
- Molecular Biology
- Virology
Background:
- Avian nephroblastomas are kidney tumors induced by retroviruses.
- Understanding the genetic alterations driving tumor formation is crucial for cancer research.
Purpose of the Study:
- To identify genes involved in avian nephroblastoma development induced by the MAV2 retrovirus.
- To investigate the role of the twist gene in MAV2-induced tumorigenesis.
Main Methods:
- Analysis of MAV2 retroviral integration sites in tumor DNA.
- Quantification of twist gene expression in nephroblastoma samples.
- Comparison of gene expression in tumors with and without MAV2 integration at the twist locus.
Main Results:
- The twist gene was identified as a common integration site for the MAV2 provirus in tumor cells.
- MAV2 proviral integration upstream of the twist gene strongly upregulated its transcription (>200-fold).
- Elevated twist gene transcription was observed in most nephroblastomas, regardless of MAV2 integration at the twist locus.
Conclusions:
- MAV2 retroviral integration can deregulate genes controlling cell proliferation and differentiation in kidney blastema cells.
- Activation of twist gene expression appears to be a significant contributor to avian nephroblastoma development.
- In vivo selection favors tumor cell clones with hyperactivated twist gene expression.
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