Signal Transduction and metabolic control in Hematopoietic Development, stress response and cancer
1. Blood Stem Cell Maintenance
Hematopoietic stem cells are maintained within a microenvironment where signals from a niche are important for the maintenance of quiescence within a precursor population. Lack of such a niche-derived signal will cause loss of ?stemness? resulting in increased proliferation and eventual differentiation. We study this phenomenon in the Drosophila hematopoietic organ using genetic technologies available in this model organism (see Martinez-Agosto et al., Genes & Devl., 2007 for a review).
We have shown that the ?stemness? of these cells is maintained through the combined action of a Niche Signal, generated by Hedgehog (Hh) (Mandal et al., Nature, 2007), a local signal generated by Wingless/Wnt (Sinenko et al., Dev. Cell., 2009) and a reverse signal from the differentiated cells to the stem cells that we have termed the Equilibrium Signal. Several important concepts underlying Drosophila blood development have allowed us to propose this system as an appropriate genetic model for vertebrate hematopoiesis and these molecular mechanisms are being explored in the laboratory.
2. Stress Response systems
Myeloid blood cells are ideal for the study of response to many kinds of stresses. Hypoxia-related factors and free radicals known as reactive oxygen species (ROS) play a role both in hematopoietic development and in stress response (Owusu-Ansah and Banerjee, Nature 2009). Similarly, the NF-kB derived inflammatory response plays a major role in the way blood cells respond to injury at distant sites. The emerging view from these studies is that basic developmental mechanisms are co-opted again for stress, injury and inflammatory responses by the myeloid hematopoietic system. Genetic analysis allows us to understand the interrelationship between these important biological phenomena that have great relevance to diseases and disorders in humans.
3. Metabolic control in Cancer pathways
In the past, our laboratory has identified components of signal transduction pathways that participate in oncogenesis (see Bonfini et al., Science, 1991; Flores et al., Cell 2000 for examples). We have also studied the role of the mitochondrion in controlling cell-cycle (Owusu-Ansah et al., Nature Genetics, 2008; Mandal et al., Dev. Cell, 2005). When cells become transformed, they choose alternate means of metabolism (a phenomenon referred to as the Warburg effect). We study the effect of signal transduction pathways on the control of cellular metabolism and the proper balance between cellular growth and metabolism that goes awry in Cancer.
4. Metabolic control of early mouse development
We also explore the control of metabolic pathways and mitochondrial activity and biogenesis during development using early mouse embryo and the embryonic stem cells derived from them as a model. There is relative lack of data on the mechanisms that control transition between various modes of metabolic activity during phases of development. Nuclear and mitochondrial activities constantly modulate each other, and the relationship between signal transduction pathways commonly studied during development, cancer and stem cell maintenance and metabolic pathways such as oxidative phosphorylation, glycolysis, mitochondrial biosynthesis and nutrient sensing are being explored. Immediate projects include determining the metabolic processes that are essential for zygotic transcription, and the switch between mitochondrial and glycolytic processes during early mouse development.
William J. Sullivan, Peter J. Mullen, Ernst W. Schmid, Aimee Flores, Milica Momcilovic,5 Mark S. Sharpley,3 David Jelinek, Andrew E. Whiteley, Matthew B. Maxwell, Blake R. Wilde, Utpal Banerjee, Hilary A. Coller, David B. Shackelford,5,10 Daniel Braas,2,8 Donald E. Ayer, Thomas Q. de Aguiar Vallim, William E. Lowry, and Heather R. Christofk, "Extracellular Matrix Remodeling Regulates Glucose Metabolism through TXNIP Destabilization", Cell 117-132 (2018).
Cho B, Spratford CM, Yoon S, Cha N, Banerjee U, Shim J, "Systemic control of immune cell development by integrated carbon dioxide and hypoxia chemosensation in Drosophila", Nature Communications 9 (1): (2018).
Nagaraj R, Sharpley MS, Yonggang Zhou Y, Chi F, Braas D, Kim R, Clark AT, Banerjee U, "Nuclear localization of mitochondrial TCA cycle enzymes as a critical step in mammalian zygotic genome activation", Cell 168 (1-2): 210-223 (2017).
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Mondal BC, Shim J, Evans CJ, Banerjee U, "Pvr expression regulators in equilibrium signal control and maintenance of Drosophila blood progenitors", eLife (2014).
Evans CJ, Liu T, Banerjee U, "Drosophila hematopoiesis: Markers and methods for molecular genetic analysis", Methods 68 (1): 242-251 (2014).
Shim J, Gururaja-Rao S, Banerjee U., "Nutritional regulation of stem and progenitor cells in Drosophila", Development 140 (23): 4647-4656 (2013).
Shim J, Mukherjee T, Mondal BC, Liu T, Young GC, Wijewarnasuriya DP, Banerjee U., "Olfactory control of blood progenitor maintenance", Cell 155 (5): 1141-1153 (2013).
Grigorian M, Liu T, Banerjee U, Hartenstein V., "The proteoglycan Trol controls the architecture of the extracellular matrix and balances proliferation and differentiation of blood progenitors in the Drosophila lymph gland", Developmental Biology 384: 301-312 (2013).
Rao S, Banerjee U., "Oncogenic pathway utilizes mitochondrial fusion machinery to support growth", Cell Cycle 11 (24): (2012).
Nagaraj R, Gururaja-Rao S, Jones KT, Slattery M, Negre N, Braas D, Christofk H, White KP, Mann R, Banerjee U., "Control of mitochondrial structure and function by the Yorkie/YAP oncogenic pathway", Genes & Development 26 (18): 2027-2037 (2012).
Freije WA, Mandal S, Banerjee U., "Expression profiling of attenuated mitochondrial function identifies retrograde signals in Drosophila", G3: Genes, Genomes, Genetics 2 (8): 843-851 (2012).
Mukherjee T, Choi I, Banerjee U., "Genetic Analysis of Fibroblast Growth Factor Signaling in the Drosophila Eye", G3: Genes, Genomes, Genetics 2: 23-28 (2012).
Mukherjee, T., Kim, W., Mandal, L., and Banerjee, U., "Interaction Between Notch and Hif-α in Development and Survival of Drosophila Blood Cells", Science 332 (6034): 1210-1213 (2011).
Mandal, S., Lindgren, A., Srivastava, A., Clark, A., and Banerjee, U., "Mitochondrial function controls proliferation and early differentiation potential of embryonic stem cells", Stem Cells 29 (3): 486-495 (2011).