|John R. Nambu
Associate Professor of Biology, University of Massachusetts
Ph.D.: Stanford University
Gene Regulation and Programmed Cell Death in Drosophila Development
Three fundamental aspects of metazoan development are pattern formation, cell differentiation, and cell death. The first two processes ensure that cells are specified correctly and acquire appropriate functional properties. The third permits the controlled elimination of cells which have failed in the first two, or that may have transient or deleterious functions. Our laboratory utilizes Drosophila as a model to study these processes. One focus is on functional analyses of a novel HMG box gene, fish-hook, which encodes a SOX protein related to SRY, the human testis determining factor. We have shown that fish is essential for proper segmentation, nervous system organization, and appendage formation. Fish DNA binding sites were identified in specific downstream target genes. The Fish protein has strong DNA bending and transcriptional activation properties. We are currently carrying out screens in yeast and flies to identify Fish-interacting proteins.
The second focus is on analyzing the regulation of programmed cell death. We are using the embryonic CNS midline cells to study the functions of several key Drosophila cell death activators. Our work has indicated that lineage specific midline cell death occurs, and is controlled by the combined functions of the related and linked reaper, head involution defective, and grim genes. Examination of mutations and use of the Gal4/UAS targeted gene expression system have revealed novel synergistic interactions between these genes, and identified gene-specific repression by cellular anti-apoptosis proteins. We are currently pursuing structure/function studies of these proteins and analyzing the functions of several other cell death regulators.
Schreader, B.A. and Nambu, J.R. 2004. A fine balance for life and death decisions. Nature Structural and Molecular Biology , 11: 386-388.
Schreader, B.A., Wang,Y., and Nambu, J.R. 2003. Drosophila morgue and the intersection between programmed cell death and ubiquitination. Apoptosis, 8: 129-139.
Wing, J.P., Schreader, B.A., Yokokura, T., Wang, Y., Andrews, P.S., Huseinovic, N., Dong, C.K., Schwartz, L.M., White, K., Nambu, J.R. 2002. Drosophila Morgue is a novel F box/ubiquitin conjugase domain protein important in grim-reaper mediated programmed cell death. Nature Cell Biol., 4: 451-456.
Wing, J.P., Karres, J.S., Ogdahl, J.L., Zhou, L., Schwartz, L.M., Nambu, J.R. . 2002. Drosophila sickle is a novel grim-reaper cell death activator. Curr. Biol., 12: 131-135.
Schwartz, L. M., J. R. Nambu and Z. Wang (2002). "Parkinsonism proteolysis and proteasomes." Cell Death Differ 9(5): 479-82.
Wing, J. P., J. S. Karres, J. L. Ogdahl, L. Zhou, L. M. Schwartz and J. R. Nambu (2002). "Drosophila sickle is a novel grim-reaper cell death activator." Curr Biol 12(2): 131-5.
Wing, J. P., B. A. Schreader, T. Yokokura, Y. Wang, P. S. Andrews, N. Huseinovic, C. K. Dong, J. L. Ogdahl, L. M. Schwartz, K. White and J. R. Nambu (2002). "Drosophila Morgue is an F box/ubiquitin conjugase domain protein important for grim-reaper mediated apoptosis." Nat Cell Biol 4(6): 451-6.
Wing, J. P., L. M. Schwartz and J. R. Nambu (2001). "The RHG motifs of Drosophila Reaper and Grim are important for their distinct cell death-inducing abilities." Mech Dev 102(1-2): 193-203.
Mukherjee, A., X. Shan, M. Mutsuddi, Y. Ma and J. R. Nambu (2000). "The Drosophila sox gene, fish-hook, is required for postembryonic development." Dev Biol 217(1): 91-106.
Ma, Y., K. Certel, Y. Gao, E. Niemitz, J. Mosher, A. Mukherjee, M. Mutsuddi, N. Huseinovic, S. T. Crews, W. A. Johnson and J. R. Nambu (2000). "Functional interactions between Drosophila bHLH/PAS, Sox, and POU transcription factors regulate CNS midline expression of the slit gene." J Neurosci 20(12): 4596-605.
Kuelzer, F., P. Kuah, S. T. Bishoff, L. Cheng, J. R. Nambu and L. M. Schwartz (1999). "Cloning and analysis of small cytoplasmic leucine-rich repeat protein (SCLP), a novel, phylogenetically-conserved protein that is dramatically up-regulated during the programmed death of moth skeletal muscle." J Neurobiol 41(4): 482-94.
Hu, Y., P. J. Cascone, L. Cheng, D. Sun, J. R. Nambu and L. M. Schwartz (1999). "Lepidopteran DALP, and its mammalian ortholog HIC-5, function as negative regulators of muscle differentiation." Proc Natl Acad Sci U S A 96(18): 10218-23.
Mutsuddi, M. and J. R. Nambu (1998). "Neural disease: Drosophila degenerates for a good cause." Curr Biol 8(22): R809-11.
Cheng, L., N. Roemer, K. A. Smyth, J. Belote, J. R. Nambu and L. M. Schwartz (1998). "Cloning and characterization of Pros45, the Drosophila SUG1 proteasome subunit homolog." Mol Gen Genet 259(1): 13-20.
Ma, Y., E. L. Niemitz, P. A. Nambu, X. Shan, C. Sackerson, M. Fujioka, T. Goto and J. R. Nambu (1998). "Gene regulatory functions of Drosophila fish-hook, a high mobility group domain Sox protein." Mech Dev 73(2): 169-82.