The diffuse neuroendocrine system includes pancreatic islets, gastrointestinal and respiratory neuroendocrine cells, thyroid C cells, adrenal medulla cells, and pituitary cells. They share common phenotypes and signaling pathways with neuronal cells. A set of transcription factors were identified, which were activated at different stages of neuroendocrine cell development. Studies aimed at the molecular mechanisms of how these transcription factors interact with each other to confer their regulatory pathway are important for neuroendocrine cell growth and differentiation. The long-term goal of this grant proposal is to understand the role of a novel zinc-finger transcription factor, IA-1, in pancreatic endocrine and neuronal cell development. The IA-1 gene is expressed primarily in fetal pancreas, fetal brain, and tumors of neuroendocrine origin. Preliminary data indicated that the IA-1 gene is developmentally regulated and functions as a DNA-binding transcriptional repressor. Using a selected and amplified random oligonucleotide binding assay and bacterially expressed GST-IA-1 carboxyl-terminal protein, we identified the consensus IA-1 binding site. The IA-1 protein binding was confirmed by competitive electrophoretic mobility shift assay. Studies on the IA-1 promoter revealed a DNasel footprint protected site between -90 to -66 bp and this site is an almost perfect match to the IA-1 consensus binding site. Therefore, it appears that IA-1 may autoregulate itself. Further sequence analysis and competition binding assays indicated that NeuroD/beta2 represents another downstream target gene for IA-1. The NeuroD/beta2 gene encodes a basic helix-loophelix transcription factor that is crucial for the development of pancreatic endocrine and neuronal cells. These results establish the importance of IA-1 to neuroendocrine cell development. Therefore, in this proposal we aim to study: 1) the mechanisms of how the IA-1 gene regulates NeuroD/beta2 gene expression, 2) whether the IA-1 gene plays an important role in neuroendocrine development in vivo, and 3) to characterize the regulatory elements in the IA-1 gene that confer a tissue-specific expression. To achieve these aims, we will use in vitro biochemical assays, transient mammalian cell transfections, yeast two-hybrid system, in vivo IA-1 gene knockout animal model, and yeast one-hybrid system. Results from this study should help us to define the interplay between the IA-1 zinc-finger transcription factor and other neuroendocrine-specific transcription factors in pancreatic endocrine and neuronal development.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Sato, Sheryl M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Louisiana State University Hsc New Orleans
Schools of Medicine
New Orleans
United States
Zip Code
Zhang, Tao; Chen, Chiachen; Breslin, Mary B et al. (2014) Extra-nuclear activity of INSM1 transcription factor enhances insulin receptor signaling pathway and Nkx6.1 expression through RACK1 interaction. Cell Signal 26:740-7
Yusuf, Dimas; Butland, Stefanie L; Swanson, Magdalena I et al. (2012) The transcription factor encyclopedia. Genome Biol 13:R24
Zhang, Tao; Saunee, Nicolle A; Breslin, Mary B et al. (2012) Functional role of an islet transcription factor, INSM1/IA-1, on pancreatic acinar cell trans-differentiation. J Cell Physiol 227:2470-9
Cai, Chuan Qi; Zhang, Tao; Breslin, Mary B et al. (2011) Both polymorphic variable number of tandem repeats and autoimmune regulator modulate differential expression of insulin in human thymic epithelial cells. Diabetes 60:336-44
Zhang, Tao; Wang, Hongwei; Saunee, Nicolle A et al. (2010) Insulinoma-associated antigen-1 zinc-finger transcription factor promotes pancreatic duct cell trans-differentiation. Endocrinology 151:2030-9
Wang, Hong-Wei; Breslin, Mary B; Chen, Chiachen et al. (2009) INSM1 promoter-driven adenoviral herpes simplex virus thymidine kinase cancer gene therapy for the treatment of primitive neuroectodermal tumors. Hum Gene Ther 20:1308-18
Zhang, Tao; Liu, Wei-Dong; Saunee, Nicolle A et al. (2009) Zinc finger transcription factor INSM1 interrupts cyclin D1 and CDK4 binding and induces cell cycle arrest. J Biol Chem 284:5574-81
Lan, Michael S; Breslin, Mary B (2009) Structure, expression, and biological function of INSM1 transcription factor in neuroendocrine differentiation. FASEB J 23:2024-33
Wang, Hong-Wei; Muguira, Michelle; Liu, Wei-Dong et al. (2008) Identification of an INSM1-binding site in the insulin promoter: negative regulation of the insulin gene transcription. J Endocrinol 198:29-39
Breslin, Mary B; Wang, Hong-Wei; Pierce, Amy et al. (2007) Neurogenin 3 recruits CBP co-activator to facilitate histone H3/H4 acetylation in the target gene INSM1. FEBS Lett 581:949-54

Showing the most recent 10 out of 15 publications