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Until recently, little detailed information was known about the factors controlling pancreas development and islet beta cell function. However, our understanding has increased greatly with the identification and molecular characterization of the islet-enriched MafA, MafB, and PDX-1 transcription factors. Gene knockouts performed on these and other pancreas-enriched factors are helping to elucidate the events influencing pancreatic morphogenesis. Because of their unique expression pattern and fundamental significance to beta cells, work here is focused on defining the transcription factors involved in controlling the expression of Pdx-1 and MafA. In addition, we are examining how transcriptional factors influence beta cell formation and function. Our recent results indicate that MafA and MafB strongly impact whether a cell becomes a producer in the islet of the insulin (beta) or glucagon (alpha) hormone. Both animal and cell culture models are used in these studies, with comprehensive and diverse methods from Cre/loxP conditional gene inactivation to mass spectrometry involved in addressing our experimental questions.

Understanding the mechanisms involved in controlling of pancreatic islet beta-cell specific transcription will likely lead to the development of therapeutic approaches that will prevent, correct, or at least delay the decline in beta cell function observed in diabetics. In fact, considerable efforts are focused on trying to develop an unlimited source of insulin-producing beta-like cells from adult and embryonic stem cells, as a consequence of success in reversing type 1 diabetes by islet transplantation. We believe that long-term success in this endeavor will require a fundamental understanding of the regulatory factors that are required for controlling the specialized genetic programs associated with beta cells. Our hope is that successful completion of our proposed studies will provide information important for generating acceptable islet-like cells for therapeutic treatment.

The beta cell biology community here is also very interactive and supportive, with eight groups meeting weekly to discuss their most recent findings. This gives students, post-docs, and faculty a routine opportunity to obtain input from a group of experts.

Publications

The following timeline graph is generated from all co-authored publications.

  1. Inactivation of specific β cell transcription factors in type 2 diabetes. Guo S, Dai C, Guo M, Taylor B, Harmon JS, Sander M, Robertson RP, Powers AC, Stein R (2013) J Clin Invest 123(8): 3305-16
    › Primary publication · 23863625 (PubMed) · PMC3726150 (PubMed Central)
  2. Characterization of an apparently novel β-cell line-enriched 80-88 kDa transcriptional activator of the MafA and Pdx1 genes. Hunter CS, Stein R (2013) J Biol Chem 288(6): 3795-803
    › Primary publication · 23269676 (PubMed) · PMC3567634 (PubMed Central)
  3. Islet α-, β-, and δ-cell development is controlled by the Ldb1 coregulator, acting primarily with the islet-1 transcription factor. Hunter CS, Dixit S, Cohen T, Ediger B, Wilcox C, Ferreira M, Westphal H, Stein R, May CL (2013) Diabetes 62(3): 875-86
    › Primary publication · 23193182 (PubMed) · PMC3581213 (PubMed Central)
  4. The B55α-containing PP2A holoenzyme dephosphorylates FOXO1 in islet β-cells under oxidative stress. Yan L, Guo S, Brault M, Harmon J, Robertson RP, Hamid R, Stein R, Yang E (2012) Biochem J 444(2): 239-47
    › Primary publication · 22417654 (PubMed) · PMC5006628 (PubMed Central)
  5. The pancreatic islet β-cell-enriched transcription factor Pdx-1 regulates Slc30a8 gene transcription through an intronic enhancer. Pound LD, Hang Y, Sarkar SA, Wang Y, Milam LA, Oeser JK, Printz RL, Lee CE, Stein R, Hutton JC, O'Brien RM (2011) Biochem J 433(1): 95-105
    › Primary publication · 20942803 (PubMed) · PMC4130494 (PubMed Central)
  6. Islet beta-cell-specific MafA transcription requires the 5'-flanking conserved region 3 control domain. Raum JC, Hunter CS, Artner I, Henderson E, Guo M, Elghazi L, Sosa-Pineda B, Ogihara T, Mirmira RG, Sussel L, Stein R (2010) Mol Cell Biol 30(17): 4234-44
    › Primary publication · 20584984 (PubMed) · PMC2937551 (PubMed Central)
  7. Phosphorylation within the MafA N terminus regulates C-terminal dimerization and DNA binding. Guo S, Vanderford NL, Stein R (2010) J Biol Chem 285(17): 12655-61
    › Primary publication · 20208071 (PubMed) · PMC2857093 (PubMed Central)
  8. The stability and transactivation potential of the mammalian MafA transcription factor are regulated by serine 65 phosphorylation. Guo S, Burnette R, Zhao L, Vanderford NL, Poitout V, Hagman DK, Henderson E, Ozcan S, Wadzinski BE, Stein R (2009) J Biol Chem 284(2): 759-65
    › Primary publication · 19004825 (PubMed) · PMC2613637 (PubMed Central)
  9. Ptf1a binds to and activates area III, a highly conserved region of the Pdx1 promoter that mediates early pancreas-wide Pdx1 expression. Wiebe PO, Kormish JD, Roper VT, Fujitani Y, Alston NI, Zaret KS, Wright CV, Stein RW, Gannon M (2007) Mol Cell Biol 27(11): 4093-104
    › Primary publication · 17403901 (PubMed) · PMC1900007 (PubMed Central)
  10. Complementation rescue of Pdx1 null phenotype demonstrates distinct roles of proximal and distal cis-regulatory sequences in pancreatic and duodenal expression. Boyer DF, Fujitani Y, Gannon M, Powers AC, Stein RW, Wright CV (2006) Dev Biol 298(2): 616-31
    › Primary publication · 16962573 (PubMed)