Synergistic activation of the insulin gene promoter by the β-cell enriched transcription factors MafA, Beta2, and Pdx1

Aramata, Shinsaku; Han, Song‐iee; Yasuda, Kazuaki; Kataoka, Kohsuke

doi:10.1016/j.bbaexp.2005.05.009

Cited by 89 publications

(80 citation statements)

References 29 publications

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“…Maf family members also frequently cooperate with members of other transcription factor families (Ho et al, 1996,Huang et al, 2002,Rajaram and Kerppola, 2004,Sevinsky et al, 2004,Aramata et al, 2005 and can also interact with transcriptional coactivators, such as CREB-binding protein and p300 to activate gene transcription (Chen et al, 2002). In our hands co-transfection of c-Maf with either Ets-2 or c-Jun expression plasmids did not show synergistic effects between these transcription factors on the CD13 proximal promoter (data not shown).…”

Section: Discussionmentioning

confidence: 53%

CD13/APN transcription is regulated by the proto-oncogene c-Maf via an atypical response element

Mahoney

Petrović

Schacke

et al. 2007

Gene

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Angiogenic growth factors induce the transcription of the cell surface peptidase CD13/APN in activated endothelial cells of the tumor vasculature. Inhibition of CD13/APN abrogates endothelial invasion and morphogenesis in vitro and tumor growth in vivo suggesting a critical functional role for CD13 in angiogenesis. Experiments to identify the transcription factors responsible for this regulation demonstrated that exogenous expression of the proto-oncogene c-Maf, but not other bZip family members tested, potently activates transcription from a critical regulatory region of the CD13 proximal promoter between −115 and −70 bp which is highly conserved among mammalian species. Using promoter mutation, EMSA and ChIP analyses we established that both endogenous and recombinant c-Maf directly interact with an atypical Maf response element contained within this active promoter region via its basic DNA/leucine zipper domain. However full activity of c-Maf requires the amino-terminal transactivation domain, and site-directed mutation of putative phosphorylation sites within the transactivation domain (serines 15 and 70) shows that these sites behave in a dramatic cell type-specific manner. Therefore, this atypical response element predicts a broader range of c-Maf target genes than previously appreciated and thus impacts its regulation of multiple myeloma as well as endothelial cell function and angiogenesis.

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Section: Discussionmentioning

confidence: 53%

CD13/APN transcription is regulated by the proto-oncogene c-Maf via an atypical response element

Mahoney

Petrović

Schacke

et al. 2007

Gene

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“…However, two key factors may have contributed to these observations: firstly, the promoter experiments were performed over 24 h, by which time nuclear IPF1 levels have dropped and DNA binding activity has decreased. Secondly, it has become increasingly clear that regulation of the proinsulin promoter is controlled through the synergistic activities of a number of beta cell transcription factors [37][38][39]. Hence, activation of IPF1 alone may not be sufficient to effect proinsulin gene transcription in this case.…”

Section: Discussionmentioning

confidence: 99%

Effects of rosiglitazone and metformin on pancreatic beta cell gene expression

et al. 2006

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Aims/hypothesis: Rosiglitazone and metformin are two oral antihyperglycaemic drugs used to treat type 2 diabetes. While both drugs have been shown to improve insulin-sensitive glucose uptake, the direct effects of these drugs on pancreatic beta cells is only now beginning to be clarified. The aim of the present study was to determine the direct effects of these agents on beta cell gene expression. Methods: We used reporter gene analysis to examine the effects of rosiglitazone and metformin on the activity of the proinsulin and insulin promoter factor 1 (IPF1) gene promoters in the glucose-responsive mouse beta cell line Min6. Western blot and gel retardation analyses were used to examine the effects of both drugs on the regulation of IPF1 protein production, nuclear accumulation and DNA binding activity in both Min6 cells and isolated rat islets of Langerhans. Results: Over 24 h, rosiglitazone promoted the nuclear accumulation of IPF1 and forkhead homeobox A2 (FOXA2), independently of glucose concentration, and stimulated a two-fold increase in the activity of the Ipf1 gene promoter (p<0.01). Stimulation of the Ipf1 promoter by rosiglitazone was unaffected by the presence of the peroxisome proliferator activated receptor γ antagonist GW9662. No effect of either rosiglitazone or metformin was observed on proinsulin promoter activity. Metformin stimulated IPF1 nuclear accumulation and DNA binding activity in a time-dependent manner, with maximal effects observed after 2 h. Conclusions/interpretation: Metformin and rosiglitazone have direct effects on beta cell gene expression, suggesting that these agents may play a previously unrecognised role in the direct regulation of pancreatic beta cell function.

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“…The bZIP factors MafA/B are expressed relatively later in development and are essential to acquire and maintain the mature state of hormone-expressing cells by activating genes important for b-cell function. These genes include insulin, Pdx1, GLUT2, Nkx6.1, Slc30a8 (zinc transporter) and G6pc2 (Glucose-6-phosphatase catalytic sub-unit 2 protein) (Aramata et al, 2005;Zhao et al, 2005, Raum et al, 2006Artner et al, 2007). During development, b-cells move from a MafB þ immature state to MafA þ / MafB þ , and finally, to a MafA þ mature state.…”

Section: Class Iii: Maturation Factorsmentioning

confidence: 99%

Pancreas organogenesis: From bud to plexus to gland

Pan

Wright

2011

Developmental Dynamics

525

594

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Pancreas oganogenesis comprises a coordinated and highly complex interplay of signaling events and transcriptional networks that guide a step-wise process of organ development from early bud specification all the way to the final mature organ state. Extensive research on pancreas development over the last few years, largely driven by a translational potential for pancreatic diseases (diabetes, pancreatic cancer, and so on), is markedly advancing our knowledge of these processes. It is a tenable goal that we will one day have a clear, complete picture of the transcriptional and signaling codes that control the entire organogenetic process, allowing us to apply this knowledge in a therapeutic context, by generating replacement cells in vitro, or perhaps one day to the whole organ in vivo. This review summarizes findings in the past 5 years that we feel are amongst the most significant in contributing to the deeper understanding of pancreas development. Rather than try to cover all aspects comprehensively, we have chosen to highlight interesting new concepts, and to discuss provocatively some of the more controversial findings or proposals. At the end of the review, we include a perspective section on how the whole pancreas differentiation process might be able to be unwound in a regulated fashion, or redirected, and suggest linkages to the possible reprogramming of other pancreatic cell-types in vivo, and to the optimization of the forward-directed-differentiation of human embryonic stem cells (hESC), or induced pluripotential cells (iPSC), towards mature b-cells. Developmental Dynamics 240:530-565,

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Synergistic activation of the insulin gene promoter by the β-cell enriched transcription factors MafA, Beta2, and Pdx1

Cited by 89 publications

References 29 publications

CD13/APN transcription is regulated by the proto-oncogene c-Maf via an atypical response element

CD13/APN transcription is regulated by the proto-oncogene c-Maf via an atypical response element

Effects of rosiglitazone and metformin on pancreatic beta cell gene expression

Pancreas organogenesis: From bud to plexus to gland

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