Related Experiment Videos
Transformation by homeobox genes can be mediated by selective transcriptional repression
1Laboratory of Molecular Immunology, Howard Hughes Medical Institute, Rockfeller University.
Abstract:
Altered transcription is a recurrent theme in the field of cancer biology. But despite the central role of transcription in transformation, little is known about the mechanism by which dominant nuclear oncogenes induce malignancies. Homeobox family proteins are prominent examples of transcriptional regulators which control development and can function as oncogenes. Here we explore the molecular basis for transformation by this class of regulators using Oct-2 and Oct-1. We show that the DNA binding POU domains of these proteins are selective and sequence-specific transcriptional repressors that produce malignant lymphomas when they are expressed in T cells of transgenic mice. Mutagenesis experiments identified a specific set of promoters, those containing octamer regulatory elements, as the targets for transformation by selective inhibition of gene expression.
Insights
Homeobox proteins like Oct-2 and Oct-1 act as oncogenes by repressing gene expression. When expressed in T cells, these transcriptional repressors cause malignant lymphomas in mice.
Area of Science:
- Cancer Biology
- Molecular Oncology
- Gene Regulation
Background:
- Altered transcription is a hallmark of cancer.
- The mechanisms by which nuclear oncogenes induce malignancies are not fully understood.
- Homeobox proteins are key developmental regulators and can function as oncogenes.
Purpose of the Study:
- To investigate the molecular basis of transformation mediated by homeobox proteins, specifically Oct-2 and Oct-1.
- To elucidate how these proteins function as oncogenes.
Main Methods:
- Utilized transgenic mice expressing Oct-2 and Oct-1 in T cells.
- Performed mutagenesis experiments to identify target promoters.
- Analyzed DNA binding POU domains for sequence specificity.
Main Results:
- Oct-2 and Oct-1 function as selective, sequence-specific transcriptional repressors.
- Expression of these proteins in T cells of transgenic mice led to the development of malignant lymphomas.
- Identified promoters with octamer regulatory elements as specific targets.
Conclusions:
- The POU domains of Oct-2 and Oct-1 are critical for their oncogenic activity.
- Selective repression of gene expression at octamer elements drives lymphomagenesis.
- This study reveals a novel mechanism of oncogenesis through targeted transcriptional repression.