Courey Summary

Professor of Biochemistry

BA, Oberlin College; PhD, Harvard University; American Cancer Society Post-doctoral Fellowship; Searle Scholars Award; Basil O'Connor Starter Scholar Research Award; Member of UCLA Molecular Biology Institute.

Research

SPATIAL REGULATION OF TRANSCRIPTION IN DEVELOPMENT

Drosophila and human development are homologous processes. They utilize closely related genes working in highly conserved regulatory networks. Unlike humans, Drosophila is subject to easy genetic manipulation. As a result, most of what we know about the molecular basis of animal development has come from studies of model systems such as Drosophila.

During embryogenesis, a cluster of apparently undifferentiated cells is transformed into an ordered array of differentiated tissues. Using Drosophila as a model system, my research group studies the initial phase of this transformation in which a homogeneous field of cells is divided into a few broad domains. The initial subdivision of the Drosophila embryo depends on maternally expressed transcription factors that are synthesized, modified, and transported in ways that result in gradients of transcription factor activity (6, 17). These transcription factor gradients generate discrete domains of expression of a small number of genes in the early embryo. We are focusing on the molecular interactions that allow these maternally-encoded transcription factors to generate spatially regulated patterns of transcription.

Essentially all the regulatory circuits we study are conserved throughout the animal kingdom. Therefore, our studies have important implications for human health and development. Examples include the following:

Dorsal/ventral pattern formation. We have been extensively examining mechanisms of activation and repression by the Dorsal morphogen, a transcription factor that determines the dorsal/ventral axis during early development. This factor is the Drosophila homolog of the vertebrate regulatory protein NF-kappaB. Like Dorsal, NF-kappaB is involved in both the determination of embryonic polarity and in the innate immune response. Furthermore, both Dorsal and NF-kappaB are regulated by homologous signal transduction cascades that control transcription factor activity by regulating nuclear import.

Mechanism of Groucho-mediated repression. Groucho is a corepressor protein with ubiquitous conserved developmental roles in Drosophila and vertebrates. For example, as a component of the Notch signaling pathway, this factor has critical roles in neuronal development. In addition, as an important player in the Toll and Wnt/Wingless signaling pathways, it is required for embryonic pattern formation in both flies and humans.

Terminal pattern formation. Patterning of the embryonic termini (i.e., the head and tail) is regulated by a receptor tyrosine kinase, which signals through the Ras GTPase to control the expression of several zygotically active regulatory genes. Similar Ras pathways play roles in a myriad of biological processes in all eukaryotic organisms. For example, Ras pathways play important roles in controlling cell proliferation. As a result, mutations in Ras can lead to cancer by resulting in unchecked cell growth.

Biological role of Smt3 conjugation. Smt3 is a relatively recently discovered member of the ubiquitin family that is conserved throughout all eukaryotes. Very little is known about the function of this polypeptide modifier. Using the Drosophila model system, we are attempting to learn about the roles of Smt3 in such processes as embryogenesis and oncogenesis.

Representative Publications

1) Pan, D. J., J. D. Huang, and A. J. Courey. 1991. Functional Analysis of the Drosophila twist Promoter Reveals a Dorsal-Binding Ventral Activator Region. Gene Develop 5: 1892-1901.

2) Pan, D., and A. J. Courey. 1992. The same dorsal binding site mediates both activation and repression in a context-dependent manner. EMBO J 11: 1837-42.

3) Huang, J., D. H. Schwyter, J. M. Shirokawa, and A. J. Courey. 1993. The Interplay Between Multiple Enhancer and Silencer Elements Defines the Pattern of Decapentaplegic Expression. Gene Develop 7: 694-704.

4) Liaw, G. J., E. Steingrimsson, F. Pignoni, A. J. Courey, and J. A. Lengyel. 1993. Characterization of Downstream Elements in a Raf-1 Pathway. Proc Natl Acad Sci USA 90: 858-862.

5) Pan, D., S. A. Valentine, and A. J. Courey. 1994. The bipartite D. melanogaster twist promoter is reorganized in D. virilis. Mech Dev 46: 41-53.

6) Courey, A. J., and J. Huang. 1995. The establishment and interpretation of transcription factor gradients in the Drosophila embryo. Biochimica et Biophysica Acta 1261: 1-18.

7) Huang, J. D., T. Dubnicoff, G. J. Liaw, Y. Bai, S. A. Valentine, J. M. Shirokawa, J. A. Lengyel, and A. J. Courey. 1995. Binding sites for transcription factor NTF-1/Elf-1 contribute to the ventral repression of decapentaplegic. Genes Dev 9: 3177-89.

8) Liaw, G. J., K. M. Rudolph, J. D. Huang, T. Dubnicoff, A. J. Courey, and J. A. Lengyel. 1995. The torso response element binds GAGA and NTF-1/Elf-1, and regulates tailless by relief of repression. Genes Dev 9: 3163-76.

9) Schwyter, D. H., J. Huang, and A. J. Courey. 1995. The decapentaplegic Core Promoter Region Plays an Integral Role in the Spatial Control of Transcription. Molecular and Cellular Biology 15: 3960-8.

10) Dubnicoff, T., S. A. Valentine, G. Chen, T. Shi, J. A. Lengyel, Z. Paroush, and A. J. Courey. 1997. Conversion of dorsal from an activator to a repressor by the global corepressor Groucho. Genes Dev 11: 2952-7.

11) Rudolph, K. M., G. J. Liaw, A. Daniel, P. Green, A. J. Courey, V. Hartenstein, and J. A. Lengyel. 1997. Complex regulatory region mediating tailless expression in early embryonic patterning and brain development. Development 124: 4297-308.

12) Shirokawa, J. M., and A. J. Courey. 1997. A direct contact between the dorsal rel homology domain and Twist may mediate transcriptional synergy. Mol Cell Biol 17: 3345-55.

13) Chen, G., P. H. Nguyen, and A. J. Courey. 1998. A role for Groucho tetramerization in transcriptional repression. Molecular and Cellular Biology 18: 7259-68.

14) Valentine, S. A., G. Chen, T. Shandala, J. Fernandez, S. Mische, R. Saint, and A. J. Courey. 1998. Dorsal-mediated repression requires the formation of a multiprotein repression complex at the ventral silencer. Molecular and Cellular Biology 18: 6571-6583.

15) Bhaskar, V., S. A. Valentine, and A. J. Courey. 2000. A functional interaction between Dorsal and the components of the Smt3-conjugation machinery. Journal of Biological Chemistry 275: 4033-4040.

16) Chen, G., J. Fernandez, S. Mische, and A. J. Courey. 1999. A functional interaction between the histone deacetylase Rpd3 and the co-repressor Groucho in Drosophila development. Genes and Development 13: 2218-30.

17) Flores, R. D., and A. J. Courey. 2000. Regulation of dorsal/ventral patterning in the Drosophila embryo by multiple Dorsal-interacting proteins. Cell Biochemistry and Biophysics in press.

18) Chen, G. and A. J. Courey. 2000. Groucho/TLE family proteins and transciptional repression. Gene 249: 1-16.

19) Flores-Saaib, R. and A. J. Courey. 2000. Analysis of Groucho: Histrone interactions suggests mechanistic similarities between Goucho- and Tupl- mediated repression. Nucleic Acids Res 28: in press.

Contact Info

Department of Chemistry & Biochemistry
Graduate Program in Biochemistry and Molecular Biology
UCLA
Box 951569 (post)
607 Charles E. Young Drive East (courier)
Los Angeles, CA 90095-1569

Phone: 825-2530

Fax: 206-4038

Email: courey@chem.ucla.edu

Group

Current members of Courey lab

Ruben Flores - flores@chem.ucla.edu
Guoqing Chen - guoqing@chem.ucla.edu
Vinay Bhaskar - vinay@chem.ucla.edu
Songtao Jia - sjia@ucla.edu
Matthew Smith - msmith@chem.ucla.edu

Former members of Courey lab

Duojia Pan - DPAN@mednet.swmed.edu
Jian-Dong Huang - jdhuang@hkucc.hku.hk
Todd Dubnicoff - dubnicoff@entelos.com
Jill Shirokawa - shirokjm@email.uc.edu
Scott Valentine - scott.valentine@cp.Novartis.com
Deborah Schwyter - schwyter_deborah@smc.edu
Gwo-Jen Liaw - gjliaw@ym.edu.tw
Linda Wu - Linda.Wu.B@bayer.com

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