Carl S. Thummel, Ph.D.
Professor

Contribution to Society

Although extensive evidence links steroid hormone receptors to cancer, the downstream steps by which abnormal receptor function leads to carcinogenesis are not yet defined. Insights into the molecular mechanisms of steroid hormone function should provide a clearer understanding of how these receptors control both normal and abnormal pathways of growth and development.

Research Summary

Our lab is studying the molecular mechanisms of steroid hormone action during development. Biochemical and functional studies of vertebrate nuclear hormone receptors have led to extensive characterization of their hormone and DNA binding properties and effects on transcription. Our understanding of the later steps in hormone action, however, is relatively primitive; we know that hormones control growth, metabolism, and development, but the actual molecular mechanisms involved remain obscure.

We have chosen the fruit fly, Drosophila melanogaster, as a model system for studying the molecular mechanisms of steroid hormone action. Drosophila offers several unique advantages for our studies. First, ecdysteroids are the only steroid hormones known in the fly Ð a simplification from the multiple steroid hormones present in vertebrates. Second, like its vertebrate counterparts, the physiologically active ecdysteroid, ecdysone, is a true steroid hormone. It is derived from cholesterol and is secreted from an endocrine gland at specific times during development. It interacts with a receptor protein that has properties similar to vertebrate steroid hormone receptors, and this ecdysone-receptor protein complex binds to specific DNA sequences to induce the transcription of target genes. Third, the technical advantages of working with Drosophila allow us to use classical genetics, molecular biology, and biochemistry to dissect the regulatory mechanisms involved in controlling gene expression. As a result of these advantages, we know more about the molecular mechanisms of ecdysone action in Drosophila than is known about hormone signaling in any other organism.

Ecdysone is the key signal that triggers the major postembryonic transitions during the life cycle of the fly. We are focusing our attention on the role of ecdysone in initiating metamorphosis. At this time, pulses of ecdysone induce transcription factors that, in turn, coordinate the expression of downstream target genes. These changes in gene expression direct the animal through the remarkable developmental changes associated with metamorphosis.

During metamorphosis, ecdysone signals the destruction of most of the tissues that the larva used for its survival and growth. These obsolete tissues are replaced by adult tissues and structures that differentiate from small clusters of diploid progenitor cells. One effort in our lab is to understand how ecdysone directs these developmental pathways through the induction of stage- and tissue-specific genetic regulatory hierarchies. We have found that the destruction of larval tissues is a steroid-triggered programmed cell death response that has many of the hallmark features of apoptosis. We have also identified death regulators that play a key role in controlling larval cell death, as well as several ecdysone-induced transcription factors that appear to directly regulate these death genes. These studies provide, for the first time, a direct link between a hormonal signal and a programmed cell death response. This not only provides a molecular mechanism for understanding how ecdysone directs the destruction of larval tissues during metamorphosis, but also provides a model system for understanding how cell death can be regulated by steroid hormones. We are also using genetic screens to identify key regulators that are required for the development of adult tissues in response to ecdysone during metamorphosis.

Finally, a major focus in our lab is aimed at understanding the functions of nuclear receptor superfamily members. Although some of these proteins function as hormone-dependent transcription factors, most appear to function as constitutive transcriptional regulators, in a hormone-independent manner. One of these genes, βFTZ-F1, determines the stage-specificity of the genetic response to ecdysone. This is the first description of a regulator of the stage-specificity of hormone responses and, thus, provides a unique opportunity to understand the molecular basis of this function. Many of these nuclear receptors also appear to heterodimerize with one another and several efforts are underway to determine the functional significance of these protein-protein interactions. These studies provide a foundation for understanding how nuclear receptor superfamily members can transduce hormonal signals during development.

Recent Publications

King-Jones, K., Charles, J.-P., Lam, G. and C.S. Thummel (2005) The ecdysone-induced DHR4 orphan nuclear receptor coordinates growth and maturation in Drosophila. Cell, 121: 773-784.

Beckstead, R.B. and C.S. Thummel (2006) Indicted – C. elegans caught using steroids.  Cell, 124: 1137-1140.

King-Jones, K. and C.S. Thummel (2005) Nuclear receptors – a perspective from Drosophila. Nature Reviews Genetics, 6: 311-323.
 
Yin, V.P. and C.S. Thummel (2005) Mechanisms of steroid-triggered programmed cell death in Drosophila. Sem. in Cell and Dev. Biol., 16: 237-243.
 
C.S. Thummel (2005) Powered by gas – a ligand for a fruit fly nuclear receptor.  Cell, 122: 151-153.
 
Beckstead, R.B., Lam, G., and C.S. Thummel (2005) The genomic response to 20-hydroxyecdysone at the onset of Drosophila metamorphosis. Genome Biology, 6: R99.
 
King-Jones, K. and C.S. Thummel (2005) Less steroids make bigger flies. Science, 310: 630-631.
 
Yin, VP and Thummel, CS (2004) A balance between the diap1 death inhibitor and reaper and hid death inducers controls steroid-triggered cell death in Drosophila. Proc. Natl. Acad. Sci. USA, 101: 8022-8027.

Gates, J, Lam, G, Ortiz, JA, Losson, R, and Thummel, CS (2004) rigor mortis encodes a novel nuclear receptor interacting protein required for ecdysone signaling during Drosophila larval development. Development, 131: 25-36.

Ward, RE, Evans, J, and Thummel, CS (2003) Genetic modifier screens in Drosophila demonstrate a role for Rho1 signaling in ecdysone-triggered imaginal disc morphogenesis. Genetics, 165: 1397-1415.

Sullivan, AA, and Thummel, CS (2003) Temporal profiles of nuclear receptor gene expression reveal coordinate transcriptional responses during Drosophila development. Mol. Endocrinology, 17: 2125-2137.

Astle, J, Kozlova, T, and Thummel, CS (2003) Essential roles for the Dhr78 orphan nuclear receptor during molting of the Drosophila tracheal system. Ins. Biochem. Mol. Biol., 33: 1201-1209.

Kozlova, T and Thummel, CS (2003) Essential roles for ecdysone signaling during Drosophila mid-embryonic development. Science, 301: 1911-1914. (selected for prepublication on ScienceExpress).

Baker, KD, Shewchuk, LM, Kozlova, T, Makishima, M, Hassell, A, Wisely, B, Caravella, JA, Lambert, MH, Reinking, JL, Krause, H, Thummel, CS, Willson, TM, and Mangelsdorf, DJ (2003) The Drosophila orphan nuclear receptor DHR38 mediates an atypical ecdysteroid signaling pathway. Cell, 113: 731-742 (Science Editors' Choice vol. 300, pg. 1623).

Bashirullah, A, Pasquinelli, AE, Kiger, AA, Perrimon, N, Ruvkun, G and Thummel, CS (2003) Coordinate regulation of small temporal RNAs at the onset of Drosophila metamorphosis. Dev. Biol., 259: 1-8.

Kozlova, T, and Thummel, CS (2003) Methods to characterize Drosophila nuclear receptor activation and function in vivo. In: Methods in Enzymology. Nuclear Receptors, Vol. 364 (Russell, D.W., and Mangelsdorf, D.J., eds.), Academic Press, New York, pp. 475-490.

King-Jones, K and Thummel, CS (2003) Drosophila nuclear receptors. In "Handbook of Cell Signaling," Vol. 3, (Bradshaw, R. and Dennis, E., eds.), Academic Press, New York, pp. 69-73

Ward, R.E., Reid, P., Bashirullah, A., D’Avino, P.P. and C.S. Thummel (2003) GFP in living animals reveals dynamic developmental responses to ecdysone during Drosophila metamorphosis. Dev. Biol., 256: 389-402.

Lehmann, M., Jiang, C., Ip, Y.T., and C.S. Thummel (2002) AP-1, but not NF-?B, is required for efficient steroid-triggered cell death in Drosophila, Cell Death & Differentiation, 9: 581-590.

Kozlova, T. and C.S. Thummel (2002) Spatial patterns of Drosophila ecdysteroid receptor activation during the onset of metamorphosis, Development, 129: 1739-1750.

Bialecki, M., Shilton, A., Fichtenberg, C., Segraves, W.A., and C.S. Thummel (2002) Loss of the ecdysteroid-inducible E75A orphan nuclear receptor uncouples molting from metamorphosis in Drosophila, Dev. Cell, 3: 209-220.

Thummel, C.S. and J. Chory (2002) Steroid signaling in plants and insects – common themes, different pathways. Genes and Dev., 16: 3113-3129.

Thummel, C.S. (2001) Molecular mechanisms of developmental timing in C. elegans and Drosophila. Dev. Cell, 1:453-465.

Jiang, C., Lamblin, A.-F., Steller, H., and C.S. Thummel (2000) A steroid-triggered transcriptional hierarchy controls salivary gland cell death during Drosophila metamorphosis. Molecular Cell, 5: 445-455.

D’Avino, P.P. and C.S. Thummel (2000) The ecdysone regulatory pathway controls wing morphogenesis and integrin expression during Drosophila metamorphosis. Dev. Biology, 220: 211-224.

Lee, C.-Y., Wendel, D.P., Reid, P., Lam, G., Thummel, C.S., and E.H. Baehrecke (2000) E93 directs steroid-triggered programmed cell death in Drosophila. Molecular Cell, 6:433-443.

Kozlova, T., and C.S. Thummel (2000) Steroid regulation of postembryonic development and reproduction in Drosophila. Trends in Endo. and Metab., 11: 276-280 (cover article).

Lam, G., and C.S. Thummel (2000) Inducible expression of double-stranded RNA directs specific genetic interference in Drosophila. Current Biology, 10:957-963.

Gates, J. and C.S. Thummel (2000) An enhancer trap screen for ecdysone-inducible genes required for Drosophila adult leg morphogenesis. Genetics, 156: 1765-1776.

Jiang, C., Lamblin, A.-F., Steller, H., and C.S. Thummel (2000) A steroid-triggered transcriptional hierarchy controls salivary gland cell death during Drosophila metamorphosis. Molecular Cell, 5: 445-455.

D'Avino, P.P. and C.S. Thummel (2000) The ecdysone regulatory pathway controls wing morphogenesis and integrin expression during Drosophila metamorphosis. Dev. Biology, 220: 211-224.

Baker, K.D., Warren, J.T., Thummel, C.S., Gilbert, L.I., and D.J. Mangelsdorf (2000) Transcriptional activation of the Drosophila ecdysone receptor by insect and phytoecdysteroids. Ins. Biochem. Mole. Biol., 30: 1037-1043.

Lee, C.-Y., Wendel, D.P., Reid, P., Lam, G., Thummel, C.S., and E.H. Baehrecke (2000) E93 directs steroid-triggered programmed cell death in Drosophila. Molecular Cell, 6:433-443.

Vaskova, M., Bentley, A.M., Marshall, S., Reid, P., Thummel, C.S., and A.J. Andres (2000) Genetic analysis of the Drosophila 63F early puff: characterization of mutations in E63-1 and maggie, a putative TOM22. Genetics, 156: 229-244.

Kozlova, T., and C.S. Thummel (2000) Steroid regulation of postembryonic development and reproduction in Drosophila. Trends in Endo. and Metab., 11: 276-280.

Lam, G., and C.S. Thummel (2000) Inducible expression of double-stranded RNA directs specific genetic interference in Drosophila. Current Biology, 10:957-963.

Broadus, J., McCabe, J.R., Endrizzi, B., Thummel, C.S., and C.T. Woodard. (1999) The Drosophila §FTZ-F1 orphan nuclear receptor provides competence for stage-specific responses to the steroid hormone ecdysone. Molecular Cell, 3: 143-149.

Thummel, C.S. (1999) Ecdysone. In: "Encyclopedia of Molecular Biology"; (Creighton, T.E., ed.), John Wiley and Sons Inc., New York, pp 775-779.

D'Avino, P.P. and C.S. Thummel (1999) Ectopic expression systems in Drosophila. In: "Methods in Enzymology. Expression of Recombinant Genes in Eukaryotic Systems," Vol. 306 (Abelson, J.N., Simon, M.I., eds.), Academic Press, New York, 129-142.

Lam, G., Hall, B.L., Bender, M., and C.S. Thummel. (1999) DHR3 is required for the prepupal-pupal transition and differentiation of adult structures during Drosophila metamorphosis. Dev. Biology, 212: 204-216.

Fisk, G.J. and C.S. Thummel (1998) The DHR78 nuclear receptor is required for ecdysteroid signaling during the onset of Drosophila metamorphosis. Cell, 93: 543-555.

Hall, B.L. and C.S. Thummel (1998) The RXR homolog Ultraspiracle is an essential component of the Drosophila ecdysone receptor. Development, 125: 4709-4717.