The long-range goal of our research is to determine the physiological role of both the ELL and MLL proteins and their complexes in regulation of gene expression. Understanding the regulation of gene expression is essential for our comprehension of pathogenesis and the treatment of human cancer. Much of the regulation of gene expression important for growth and development occurs at the level of transcription. We have identified a class of transcription regulatory factors, the ELL family, which includes ELL, ELL2, and ELL3. The ELL gene undergoes frequent translocations with the MLL gene leading to the development of leukemia. We have demonstrated that ELL is required for the transforming activity of the MLL-ELL chimera. We hypothesize that ELL may function in the MLL-ELL chimera to alter MLL's transcriptional activation properties. Because of its relationship to ELL, we have also studied the role of MLL in cellular regulation. The Drosophila homologue of the MLL protein is the product of the trithorax gene (trx). The Trithorax protein is a putative DNA binding protein, which is involved in positive regulation of developmentally regulated genes. Very little is known about the human MLL protein. The MLL gene has been implicated in several hematological malignancies. We have found that the MLL protein and the MLL-ELL chimera exist in large macromolecular complexes. We plan to identify and characterize the gene products associated with MLL in these complexes in order to define their role in the regulation of gene expression. Our three Specific Aims and a brief description of methods are described below:
Aim 1. To determine the role of the MLL and MLL-ELL complexes and subunits of these complexes in the regulation of gene expression using in vitro transcription and purified proteins.
Aim 2. To correlate the functional domains of ELL proteins with cell transformation, and to define the role of the ELL associated proteins in this process using a cell transformation system and chimeric proteins.
Aim 3. To test the role of the ELL C-terminal domain-dependent dimerization in MLL-ELL chimera mediated cell immortalization, using a cell transformation system. We will use a variety of modern biochemical, enzymological, and molecular biological tools to achieve the above proposed aims. Focusing on the ELL and MLL transcription factors gives our laboratory a unique entry point to attack the related problems of transcriptional regulation and oncogenesis. These studies should: i) help to improve our understanding of the global regulation of transcription by factors such as ELL and MLL; ii) shed light on why ELL translocations into MLL result in the development of human leukemia; iii) provide information about other novel factors that associate with the MLL protein; and iv) expand our knowledge of the physiological role of the MLL gene product and its involvement in multiple hematological malignancies.
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