The major interest in my laboratory is to understand the fundamental mechanism of transcriptional regulation that control expression of genes during cell proliferation in mammalian cells. The promoters of many mammalian genes that are required for cell growth contain binding sites for the heterotrimeric CCAAT-binding transcription factor CBF/NF-Y. We studied the function of CBF by using a dominant negative CBF mutant and also by conditional inactivation of CBF-B gene in mouse cells. This showed that inactivation of CBF leads to cell growth arrest and subsequently induction of apoptotic cell death.

Comparison of mammalian promoters showed that multiple CBF binding sites are present in the promoters of two classes of genes that are activated by two different cellular pathways. One class of gene consists of topoisomerase IIalpha, cyclin B, aurora A that are activated during G2/M phase of the cell cycle, and the other class of genes consists of GRP78/BiP and protein disulfide isomerase that are activated by endoplasmic reticulum (ER) stress or unfolded protein response. Using chromatin immunoprecipitation analysis we showed that CBF interacts to the promoters of both classes of genes. This suggests that CBF directly regulates expression of genes that play role in endoplasmic reticulum function and cell cycle.

Expression of a truncated CBF-B subunit lacking transcription activation domain in human cells resulted cell growth arrest specifically at G2/M phase of the cell cycle, and inhibition of expression of topoisomerase IIalpha, cyclin B1 and aurora A at G2/M phase of the cell cycle. This suggests that the activation domain of CBF-B plays a specific role in transcription at G2/M phase of the cell cycle. Recent study demonstrated that a bZIP transcription factor ATF6, which is normally localized in ER is processed during stress and is translocated to nucleus. ATF6 does not bind to DNA by itself but requires CBF to form a DNA-protein complex. This observation led us to speculate that CBF controls transcription of various genes through recruitment of promoter specific factor(s), which is regulated by either ER stress or cell cycle. Our current goal is to establish a mechanism by which CBF-ATF6-DNA complex activates transcription during ER stress, and to develop strategy to identify factor(s), which is responsible for CBF-dependent transcription activation during G2/M phase of the cell cycle.

Recent publications

• C. Chattopadhyay, D. Hawke, R. Kobayashi, and S. N. Maity (2004) Human p32, interacts with B subunit of the CCAAT-binding factor, CBF/NF-Y, and inhibits CBF-mediated transcription activation in vitro. Nucleic Acids Research, 32:3632-3641.
  
  
• A. Bhattacharya, J.-M. Deng, Z. Zhang, R. Behringer, B. de Crombrugghe and S. N. Maity (2003) The B Subunit of The CCAAT Box Binding Transcription Factor Complex (CBF/NF-Y) is Essential for Early Mouse Development and Cell Proliferation.Cancer Research, 63:8167-8172.
  
  
• Q. Hu, C. Bhattacharya, and S. N. Maity (2002) CBF Binding Mediates Cell Cycle Activation of Topoisomerase IIa: Conventional CBF Activation Domains Are Not Required, J. Biol. Chem. 277:37191-37200.
  
  
• X. Li, C. Bhattacharya, S. Dayal, S. Maity, and W. H. Klein (2002) Ectoderm gene activation in sea embryos mediated by the CCAAT-binding factor, Differentiation, 70:109-119.
  
  
• F. Coustry, Q. Hu, B. De Crombrugghe and S. N. Maity (2001) CBF/NF-Y functions both in nucleosomal disruption and transcription activation of the chromatin-assembled topoisomerase IIa promoter: Transcription activation by CBF/NF-Y in chromatin is dependent on the promoter structure, J. Biol. Chem. 276:40621-40630.
  
  
• Hu Q, Maity SN (2000) Stable expression of a dominant negative mutant of CCAAT binding factor/NF-Y in mouse fibroblast cells resulting in retardation of cell growth and inhibition of transcription of various cellular genes. J Biol Chem 275, 4435–4444
  
  
• Maity SN, de Crombrugghe B (1998) Role of the CCAAT-binding protein CBF/NF-Y in transcription. Trends Biochem Sci 23, 174–178
  
  
• Liang SG, Maity SN (1998) Pathway of complex formation between DNA and three subunits of CBF/NF-Y. Photocross-linking analysis of DNA-protein interaction and characterization of equilibrium steps of subunit interaction and DNA binding. J Biol Chem 273, 31590–31598
  
  
• Bi W, Wu L, Coustry F, de Crombrugghe B, Maity SN (1997) DNA binding specificity of the CCAAT-binding factor CBF/NF-Y. J Biol Chem 272, 26562–26572
  
  
• Sinha S, Kim IS, Sohn K-Y, de Crombrugghe B, Maity SN (1996) Three classes of mutations in the A subunit of the CCAAT-binding factor CBF delineate functional domains involved in the three-step assembly of the CBF-DNA complex. Mol Cell Biol 16, 328-337
  
  
• Maity SN, de Crombrugghe B (1996) Purification, characterization, and role of the CCAAT binding protein CBF in transcription. Methods Enzymol 273, 217-232
  
  
• Kim IS, Sinha S, de Crombrugghe B, Maity SN (1996) Determination of functional domains in C subunit of the CCAAT-binding factor CBF necessary for formation of a CBF-DNA complex: CBF-B interacts simultaneously with both the CBF-A and CBF-C subunits to form a heterotrimeric CBF molecule. Mol Cell Biol 16, 4003-4013

Last updated 10/25/2006