Utpal Banerjee

email:  banerjee@mbi.ucla.edu
phone:  310-206-5439
office:  356 MBI
lab:  364
homepage:  http://www.mcdb.ucla.edu/Research/Banerjee/

Research Interests

Our 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, our laboratory played a key role in defining the receptor tyrosine kinase pathway through the identification of the Sos gene (1-4). 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 (5-9). 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 (10-12). 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, our 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 (13-17). 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 (18). 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 (20) and also the molecular mechanism by which stem-like cells are maintained by Hedgehog signaling from a hematopoietic niche (19-23). 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, we wish 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. In an interesting development, we have been funded by the CIRM with a seed grant with two other investigators (Teitell and Koehler) to study mitochondrial function in human ES cells. In collaboration with Amander Clark, we are pursuing these studies with a great deal of interest. Bibliography Cited (see CV for complete list) Sos 1. Karlovich, C.A., Bonfini, L., Rogge, R., Daga, A., McCallum, L., Czech, M. P., and Banerjee, U. (1995) In vivo functional analysis of the Ras exchange protein Son of sevenless. Science, 268, 576-579. 2. Baltensperger, K., Kozma, L. M., Cherniack, A. D., Karlund, J. K., Chawla, A., Banerjee, U., and Czech, M. (1993) Binding of the Ras activator son of sevenless to insulin receptor substrate-1 signaling complexes. Science, 260, 1950-1952 3. Bonfini, L., Karlovich, C. A., Dasgupta, C., and Banerjee, U. (1992) The Son of sevenless gene : A putative activator of Ras. Science, 255, 603-606. 4. Rogge, R. D., Karlovitch, C. A., and Utpal Banerjee (1991) Genetic dissection of a neurodevelopmental pathway: Son of sevenless functions downstream of sevenless and EGF receptor tyrosine kinases. Cell, 64, 39-48. Combinatorial signaling 5. Tsuda, L., Nagaraj, R., Zipursky, S. L., and Banerjee, U. (2002) The EGF Receptor, Sno and Ebi Control Delta Expression in Notch-mediated Induction. Cell, 110, 625-637. 6. Flores, G., Duan, H., Yan, H-J. Nagaraj, R., Fu, W., Zou, Y., Noll, M., and Banerjee, U. (2000) A combinatorial model of signaling in specification of cell fate. Cell, 103, 75-86. 7. Nagaraj, R., Canon, J., and Banerjee, U. (2001) Cell fate specification in the Drosophila eye. In Drosophila eye development.. Moses, K. Ed. Springer Verlag, Heidelberg 73-88. 8. Raghavendra Nagaraj and Utpal Banerjee. Combinatorial signaling in the specification of primary pigment cells in the Drosophila eye. Development (2007) 134: 825-831 9. Nagaraj, R and Banerjee, U. (2003) Reiterative and concurrent use of EGFR and Notch signaling during Drosophila eye development. Editors-in-Chief, Bradshaw and Dennis in Hand Book of Cellular Signaling, Volume 2, Elsevier Science. Chapter 258, 827-831. Mitochondria and cell cycle control 10. Owusu-Ansah, E., Yavari, A., Mandal, S.,and Banerjee, U. (2007) Distinct mitochondrial retrograde signals control the G1-S checkpoint in mitosis. Nature Genetics Resubmitted with minor revisions. 11. T.S. Vivian Liao, Gerald B. Call, Preeta Guptan, Albert Cespedes, Jamie Marshall, Kevin Yackle, Edward Owusu-Ansah, Sudip Mandal, Q. Angela Fang, Gelsey L. Goodstein, William Kim, and Utpal Banerjee. (2006) An efficient genetic screen in Drosophila to identify nuclear-encoded genes with mitochondrial function. Genetics 174(1):525-33 12. Mandal, S., Guptan, P., Owusu-Ansah, E. and Banerjee, U. (2005) Mitochondrial regulation of a Cyclin E-dependent cell cycle checkpoint as revealed by the tenured mutation in Drosophila. Developmental Cell 9: 843-854. Runx proteins in development 13. Canon, J., and U. Banerjee. (2000) Runt and Lozenge function in Drosophila development. Sem. in Cell and Devl. Biol., 11, 327-336. 14. Yan, H-J., Canon, J. and Banerjee, U. (2003) A transcriptional chain linking eye specification to terminal determination of cone cells in the Drosophila eye. Devl. Biol., 263, 323-329. 15. Kaminker, J. S., Canon, J., Salecker, I., and Banerjee, U. (2002) Control of photoreceptor axon target choice by transcriptional repression of Runt. Nature Neuroscience, 5, 746-750. 16. Kaminker,J., Singh, R., Lebestky, T., Yan, H., and Banerjee, U. (2001) Redundant Function of Runt Domain Binding Partners, Big-brother and Brother, During Drosophila Development. Development, 128, 2639-2648. 17. Canon, J. and Banerjee, U (2003) In vivo analysis of a developmental circuit for direct transcriptional activation and repression in the same cell by a Runx protein. Genes and Development, 17, 838-843. Drosophila hematopoiesis 18. Lebestky, T., Chang, T., Hartenstein, V. and Banerjee, U. (2000) Specification of Drosophila hematopoietic lineage by conserved transcription factors. Science, 288, 146-149. 19. Jung, S-H., Evans, C., Uemura, and Banerjee, U. (2005) The Drosophila lymph gland as a developmental model of hematopoiesis. Development 132: 2521-2533. 20. Mandal, L., Banerjee, U., Hartenstein, V. (2004) Evidence for a hemangioblast and similarities between lymph gland hematopoiesis in Drosophila and mammalian AGM. Nature Genetics. 36, 1019 – 1023. 21. Evans, C.J., Hartenstein, V., and Banerjee, U. (2003) Thicker than blood: conserved mechanisms in Drosophila and vertebrate hematopoeisis. Developmental Cell. 5, 673-690. 22. Lebestky, T., Jung, S-H. and Banerjee, U. (2003) A Serrate-expressing signaling center controls Drosophila hematopoiesis. Genes and Development. 17, 348-353. 23. Mandal, L., Augusto-Martinez,J., Evans, C., Hartenstein, V., and Banerjee, U. (2007) A Hedgehog and Antennapedia dependent niche controls Drosophila hematopoietic precursors. Nature 446, 320-324.

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