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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2007.12.009 Byline: Wataru Nishimura (a)(b), Sheldon Rowan (b)(c), Therese Salameh (a), Richard L. Maas (b)(c), Susan Bonner-Weir (a)(b), Susan M. Sell (d), Arun Sharma (a)(b) Keywords: MafB; MafA; Pax6; Sey; Kreisler; Insulin gene transcription factor; Pancreatic development; Endocrine differentiation; Pancreatic islets Abstract: During pancreatic development insulin.sup.+ cells co-express the transcription factors MafB and Pax6, and transition from a MafA.sup.- to MafA.sup.+ state. To examine the role of Pax6 and MafB in the development of [beta]-cells, we analyzed embryonic pancreata from Pax6- and MafB-deficient mice. Pax6 deficiency, as manifest in the Pax6.sup.Sey-Neu allele, reduced not only the number of cells expressing insulin or glucagon, but also the number of MafB, PDX-1 and MafA expressing cells. We show that MafB can directly activate expression of insulin and glucagon, and a MafB protein engineered to contain N248S mutation in the MafB (kr.sup.ENU) results in significantly reduced activation. Furthermore, pancreata from MafB deficient (kr.sup.ENU /kr.sup.ENU) mice exhibited reduced number of cells expressing insulin, glucagon, PDX-1 and MafA, with only a minor reduction in MafB expressing cells. MafB deficiency does not affect endocrine specification but does affect the lineage commitment of the endocrine cells and their maturation. Similar to Pax6 deficient mice, MafB deficient mice showed reductions both in insulin and glucagon expressing cells and in the ability of MafB and PDX-1 expressing cells to activate expression of these hormones. However, MafB deficient mice exhibited no effect on Pax6 expression. These results suggest that MafB may function as a downstream mediator of Pax6 in regulating the specification of insulin and glucagon expressing cells. Interestingly, the remaining insulin.sup.+ cells in these knockouts preferentially express Hb9, suggesting the existence of an alternate pathway for the generation of insulin expressing cells, even in the absence of Pax6 and MafB function. Thus, Pax6 acts upstream of MafB, which in turn may trigger the expression of insulin and regulate the PDX-1 and MafA expression required for [beta]-cell maturation. Author Affiliation: (a) Section of Islet Transplantation and Cell Biology, Joslin Diabetes Center, USA (b) Department of Medicine, Harvard Medical School, Boston, MA 02215, USA (c) Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA (d) Bioinformatics Research Center and Department of Biology, University of North Carolina at Charlotte, Charlotte, NC 28223, USA Article History: Received 30 August 2007; Revised 6 December 2007; Accepted 10 December 2007

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2006.02.028 Byline: Wataru Nishimura (a)(b), Takuma Kondo (a)(b), Therese Salameh (a), Ilham El Khattabi (a)(b), Rikke Dodge (a)(b), Susan Bonner-Weir (a)(b), Arun Sharma (a)(b) Keywords: MafA; MafB; Maf factors; Insulin gene transcription factor; Pancreatic development; Endocrine differentiation; Pancreatic islets Abstract: Major insulin gene transcription factors, such as PDX-1 or NeuroD1, have equally important roles in pancreatic development and the differentiation of pancreatic endocrine cells. Previously, we identified and cloned another critical insulin gene transcription factor MafA (RIPE3b1) and reported that other Maf factors were expressed in pancreatic endocrine cells. Maf factors are important regulators of cellular differentiation; to understand their role in differentiation of pancreatic endocrine cells, we analyzed the expression pattern of large-Maf factors in the pancreas of embryonic and adult mice. Ectopically expressed large-Maf factors, MafA, MafB, or cMaf, induced expression from insulin and glucagon reporter constructs, demonstrating a redundancy in their function. Yet in adult pancreas, cMaf was expressed in both [alpha]- and [beta]-cells, and MafA and MafB showed selective expression in the [beta]- and [alpha]-cells, respectively. Interestingly, during embryonic development, a significant proportion of MafB-expressing cells also expressed insulin. In embryos, MafB is expressed before MafA, and our results suggest that the differentiation of [beta]-cells proceeds through a MafB.sup.+ MafA.sup.- Ins.sup.+ intermediate cell to MafB.sup.- MafA.sup.+ Ins.sup.+ cells. Furthermore, the MafB to MafA transition follows induction of PDX-1 expression (Pdx-1.sup.high) in MafB.sup.+ Ins.sup.+ cells. We suggest that MafB may have a dual role in regulating embryonic differentiation of both [beta]- and [alpha]-cells while MafA may regulate replication/survival and function of [beta]-cells after birth. Thus, this redundancy in the function and expression of the large-Maf factors may explain the normal islet morphology observed in the MafA knockout mice at birth. Author Affiliation: (a) Section of Islet Transplantation and Cell Biology, Joslin Diabetes Center, Boston, MA 02215, USA (b) Department of Medicine, Harvard Medical School, Boston, MA 02132, USA Article History: Received 9 December 2005; Revised 27 January 2006; Accepted 16 February 2006 Article Note: (footnote) [star] Maf factors are important for pancreatic differentiation.

Change from MafB to MafA expression coming with distinction to pancreatic endocrine cells is studied.

Since current cancer therapies do not work effectively for all patients, there is a pressing need for alternate, affordable, yet effective treatments for inoperable and chemo-resistant tumors. Presented in this paper are our investigations on the application of short duration (milli and micro seconds) electrical voltage pulses for the treatment of breast carcinoma. For this purpose, electroporation, a pulse power technology, was evaluated for its effect upon the viability and proliferation of human breast cancer cells using a number of voltages and pulse durations. The results indicate the promising potential of electrical pulses to effectively and economically enhance drug transport across the normally impermeable plasma cell membranes and to reduce proliferation. [ABSTRACT FROM PUBLISHER]

During pancreatic development insulin+ cells transition from a MafA- to MafA+ state. Our previous results suggested that the expression of transcription factor MafB in insulin+ cells precedes this maturation step. To directly examine the role of MafB in this process, we analyzed embryonic pancreas from mice carrying a kreisler mutation in the mafBkr/kr gene. We show that this kr allele, for which serine is replaced by asparagine in the conserved, DNA-binding domain found in all bZIP family members, reduced the ability of MafB to activate both insulin and glucagon gene expression and that mice with this mutation had a significant reduction in the insulin and glucagon expressing cells. Mutation also resulted in the reduction of PDX-1+ and MafA+ cells with only a minor reduction in MafB+ cells. Interestingly, the proportion of MafB+ or PDX-1+ cells that also expressed insulin was reduced. However mutation in MafB did not affect the expression of Nkx2.2, Nkx6.1, Ngn3 and Pax6 suggesting that MafB does not affect the endocrine specification but rather plays a role in the maturation of insulin+ cells. Examination of Pax6 sey/sey mutant mice demonstrated a reduction in the insulin, glucagon, MatB, PDX-1 and MafA expressing cells. Since Pax6 expression was not altered in kreisler mice, our results suggest a role of MafB in the reduction of insulin and glucagon expressing cells in sey/sey mice. Furthermore, as in kreisler mice, the proportion of MafB+ or PDX-1+ cells expressing insulin was reduced in sey/sey mice, suggesting roles for both Pax6 and MafB in regulating the efficiency of terminal differentiation/maturation of insulin+ cells. Interestingly, unlike MafB and PDX-1 that were also expressed in some insulin- cells, all MafA+ cells in these mutant mice expressed insulin. Thus, our results indicate that MafA is a marker of terminally differentiated β-cell, and that Pax6 acts upstream of MafB, which in turn contributes to the expression of PDX-1 and MafA in differentiating insulin+ cells. [ABSTRACT FROM AUTHOR]