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Debabrata Chakravarti, PhD
Associate Professor & Associate Director
Division of Reproductive Biology Research (Ob/Gyn)
Leader, Hormone Action & Signal Transduction Program
Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Regulations of Cancer cell function, hormone signaling and chromatin modifications
Curricula:
Cancer Biology
Cell Biology
Molecular Biology and Genetics
E-mail: debu@northwestern.edu |
The Chakravarti laboratory is interested in understanding the roles of nuclear hormone signaling and chromatin modifications in regulating normal cell and organ physiology and how altered transcriptional signaling contributes to cancer development and metastasis. To pursue these overall goals, we are currently focusing on three research areas which are of significant current interests in biomedical field. Our work is currently funded in part by grants from the NIH (NCI and NIDDK). We are currently accepting graduate students and postdoctoral fellows in all research areas discussed below. We have “beaker-ready” rotation and thesis projects in our laboratory for prospective students. IGP students should contact Dr. Chakravarti directly about the availability of current rotation projects in the laboratory.
Research Area 1: Transcriptional Regulation of Tumor Development and Metastasis: The major cause of cancer related death is metastasis. However how altered transcriptional regulation contributes to cancer development and progression is not clearly understood. We have recently discovered and characterized a new family of proteins termed the THAP family. Using xenograft mouse model, microarray and ChIP-chip techniques, extensive analysis of human progressive cancer tissue samples, and state of the art molecular techniques, students and postdoctoral fellows in the laboratory are determining the role of this novel THAP domain transcription factor in cancer progression and metastasis. These studies should advance our knowledge of cancer progression and metastasis and may provide a molecular target for therapeutic intervention.
Research Area 2: Nuclear Hormone Receptor Signaling: Members of the nuclear receptor superfamily mediate the actions of steroid hormones and vitamins by functioning as ligand regulated transcription factors. Not surprisingly, alterations of receptor/hormone function, and coactivator and corepressor proteins have been implicated in several human diseases including cancer. We have recently shown that the chromatin remodeling and assembly protein Acf1 plays a critical role in nuclear hormone receptor function. Laboratory members are currently determining the specific and global role of Acf1 in gene regulation and cell function using biochemical, bioinformatics, ChIP, and molecular techniques.
Research Area 3: Chromatin Modifications and Effectors of “Histone Code”: Combinatorial histone modifications (Histone code) including acetylation, methylation and phosphorylation play important regulatory roles in gene expression, chromatin function, and cell cycle progression. We have recently demonstrated that the SR-proteins are critical cell cycle dependent effector proteins for histone H3 serine 10 phosphorylation. Members in the laboratory are currently investigating the mechanisms by which these “effector-modification” interactions contribute to cell cycle progression.
Selected Publications:
Seo, S-b., McNamara, P., Heo, S., Turner, A., Lane, W., and Chakravarti, D. Regulation of histone acetylation and transcription by INHAT, a human cellular complex containing the Set oncoprotein (2001). Cell, 104, 119-130, 2001.
Chakravarti, D. and Hong, R. SET-ting the stage for life and death. Cell 112, 589-591, 2003.
Hong, R., and Chakravarti, D. The human proliferating cell nuclear antigen, PCNA, regulates transcriptional coactivator p300 activity and promotes transcriptional repression. J.Biol. Chem. 278: 44505-44513, 2003.
Kutney S.N., Hong, R., Macfarlan, T., and Chakravarti, D. A signaling role of histone binding proteins and INHAT subunits pp32 and Set/TAF-I beta in integrating chromatin hypoacetylation and transcriptional repression. J.Biol. Chem. 279: 30850-30855, 2004.
Macfarlan, T., Kutney, S, Altman, B., Montross, R., Yu, J., and Chakravarti, D. Human THAP7 is a chromatin-associated, histone tail binding protein that represses transcription via recruitment of HDAC3 and nuclear hormone receptor corepressor. J.Biol. Chem 280, 7346-7358, 2005.
Macfarlan, T., Parker, J.B. Nagata, K., and Chakravarti, D. THAP7 associates with template activating factor-Ib/SET and inhibits histone acetylation to repress transcription. Mol. Endo 20, 335-347, 2006.
Ewing, A.K., Attner, M., and Chakravarti, D. Novel Regulatory Role for Human Acf1 in Transcriptional Repression of Vitamin D3 Receptor-Regulated Genes. Mol. Endo. 21, 1791-1806, 2007.
Loomis, R.J., Naoe, Y, Parker, J.B., Savic, V., Bozovsky, M., Macfarlan, T., Manley, J., and Chakravarti, D. Chromatin binding of SRp20 and ASF/SF2 and dissociation from Mitotic chromosome is modulated by histone H3 serine 10 phosphorylation. Mol. Cell. 33, 450-461, 2009.
Buranapramest, M., and Chakravarti, D. Chromatin remodeling and nuclear receptor signaling. Prog.in Mol.Biol. and Translational Science, Vol 87 (in press, 2009).
