The Banerjee laboratory uses Drosophila as a model organism to genetically dissect pathways that are important for normal development, cell cycle and cell fate control. Abnormalities in pathways investigated in the laboratory lead to developmental defects in the fly and in every case studied, have been linked to developmental defects or cancers in man. In the past, the Banerjee laboratory played a key role in defining the receptor tyrosine kinase pathway through the identification of the Sos gene. Later work concentrated on developing combinatorial signaling models that explain how signal transduction pathways, important in oncogenic transformations, cooperate in the normal cell in maintaining a homeostatic balance between proliferation, differentiation and apoptosis. These studies lead to developmental networks that connect different signal transduction pathways together and also provide in vivo examples of reiterative use of the same pathway, in the same cell, at multiple times during development, each causing a different cellular response.
In a surprising finding the above studies also unraveled a novel checkpoint regulation in mitosis that is controlled by the level of mitochondrial function in a cell. These Drosophila studies unraveled specific pathways that link the mitochondrion with the proliferation mechanism. The mitochondrion uses signaling molecules such as AMP and Reactive oxygen species (ROS) to control functions ascribed to the nucleus. Interfering with such pathways to cause a break in the communication between the mitochondrion and the nucleus could be an important strategy to prevent expansion of tumor cell growth and proliferation.
In projects that are closely linked to cancer studies in humans, the laboratory has extensively studied the mechanism by which Runx-like proteins function. The human homolog, Runx1 is linked to a very large class of acute myeloid leukemia (AML1). In studies performed over the last several years, the molecular mechanism by which such proteins can switch between an activator to a repressor of transcription was revealed. Also, determined was the nature of interactions with partner proteins that are important in the etiology of AML. Strikingly, the Runx-like proteins Lozenge and Runx-B are involved in Drosophila hematopoiesis as they are in mammalian system. This led to a full-scale investigation, in our laboratory, of blood cell development using Drosophila as a model system. Extension of this study in collaboration with Volker Hartenstein's laboratory led to the identification of a Drosophila hemangioblast population and also the molecular mechanism by which stem-like cells are maintained by Hedgehog signaling from a hematopoietic niche. The role of Hedgehog in many developmental circumstances in mammals is well established, and based on the results in flies, it will be important to study the regulation of hematopoietic proliferation and maintenance by this pathway.
The near-future plans for the laboratory include determining the molecular basis for all the interactions that keep a balance between the hematopoietic niche, the set of stem cells that they maintain and the differentiated cells that result from them. Clearly, a balance must exist between the number of cells allowed to differentiate and the ones that are maintained as precursor reserve pool. Molecular details of how this is achieved is not worked out in mammals and we hope studies in Drosophila will show the way as it has done in the past for numerous developmental systems. On the practical side, we will like to develop Drosophila as a model system for direct screening of small molecules for hematopoietic malignancies. In preliminary studies, we have found that human AML-ETO, the fusion product responsible for AML, expressed in Drosophila causes hyperplasia of blood cells. This is not true of other tissues. The effect can be either suppressed or enhanced by a single copy of second site mutations. The Cancer center small molecule screening resources will be used in an in vivo screen to determine if the phenotypes observed in flies bearing AML-ETO can either be enhanced or suppressed by application of drugs as an initial approach for in vivo screening.
On the mitochondrial side, the Banerjee laboratory wishes to determine how retrograde signals from the mitochondria might directly control a variety of cellular functions that are normally thought of as the domain of nuclear and cytoplasmic function. We have already deciphered mechanisms by which cell cycle can be influenced by mitochondrial signaling. Preliminary data suggest a role of the mitochondrion in specific differentiation steps and apoptosis. This will be analyzed further.
Intercellular interactions play a pivotal role in the development of the nervous system of all organisms. Recent studies have suggested that many aspects of cell-cell interactions involve common pathways for signal transduction. Members of such cascades include cellular oncogenes, whose malfunction can cause misregulation of growth and development. Our laboratory uses the developing eye of Drosophila as a model system since in this system, complex interactions between signal transduction pathways can be resolved into simpler genetic pathways. Work in our laboratory, and that of others has demonstrated that many of these pathways include Drosophila homologs of vertebrate oncogenes. The Son of sevenless (Sos) gene, first identified by mutational analysis in our laboratory has been found to be a link between tyrosine kinase receptors and Ras in many signalling systems across species. A significant aspect of our research also focusses on transcription factors that provide the context in which signalling cascades are interpreted. It is well known that a Ras derived signal could either cause a cell to divide or differentiate depending upon its predisposition. We have found that a transcription factor homologous to the Acute Myeloid leukemia (AML1) gene product in humans is important in allowing cells in the eye and in the hematopoietic system to interpret signals that they receive. It seems that developmental decisions involve a small number of signal transduction pathways, the outputs from which are interpreted combinatorially by the enhancer sequences of downstream genes. Our laboratory would like to understand how different signal transduction cascades are integrated to produce unique developmental responses. Through these studies, using Drosophila as a genetic model, we hope to identify basic molecular strategies that are conserved in development across species. We will exploit the similarities between zebrafish and human hematopoiesis to identify candidates for the genes mutated in the secondary steps of human leukemia. A strain of zebrafish will be engineered for predisposition to acute leukemia due to expression of a human leukemic oncogene in the hematopoietic stem cells. These mutations will be mapped, the genes molecularly cloned, and their roles in normal hematopoiesis and leukemia fully characterized.
Utpal Banerjee is currently a Distinguished Professor in the Department of Molecular, Cell & Developmental Biology at UCLA and Co-Director of the Broad Stem Cell Research Center. In 2000, the University named Utpal as one of the "Best 20 Professors" of the "Bruin Century". He was further distinguished with the Luckman and Gold Shield Awards, the highest research and teaching awards in any subject, including humanities and social sciences, at UCLA. Dr. Banerjee is among 20 professors nationally to be awarded a $1 million grant by the Howard Hughes Medical Institute (HHMI) to creatively improve undergraduate science teaching. The grant has generously funded the UCLA Undergraduate Research Consortium in Functional Genomics (URCFG). Utpal has a joint appointments in Biological Chemistry where he teaches advanced Genetics courses. Utpal received his Ph.D. in Chemistry at Caltech. His successful transition into Biology was earmarked by his postdoctoral research training with Dr. Seymour Benzer at Caltech where he initiated research in molecular neurogenetics of eye development in Drosophila and worked on the sevenless locus. As a scientist and professor, he is a dedicated and an accomplished researcher in the fields of Drosophila genetics and developmental biology. His current research interests are in signal transduction and transcriptional control of neural and hematopoietic development. Earlier work from Utpal's laboratory identified the son of sevenless (sos) gene that participates in all RTK signaling pathways. Currently his laboratory is identifying novel means by which different signal transduction cascades combine to distinguish between neural and non-neural cell types in the Drosophila eye. They have also made critical discoveries in identifying transcription factors and signaling components that are responsible for the hematopoiesis in Drosophila. Using Drosophila as a genetic model, they hope to identify basic molecular strategies that are conserved in development across species. Prof. Banerjee has authored many publications and review articles. He has served on several NIH Genetics Study Sections and has been a Scientific Advisor to several private companies and foundations. He has contributed prominently to both the academic and scientific community at UCLA. Utpal, his lovely wife, Arpita, and their fantastic kids, Mohini and Vivek, live in Los Angeles.
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