Activin A-induced expression of PAX4 in AR42J-B13 cells involves the increase in transactivation of E47/E12

Rei Kanno; Takeshi Ogihara; Yasuhiro Igarashi; Yasushi Tanaka; Stuart B. Smith; Itaru Kojima; Michael S. German; Ryuzo Kawamori; Hirotaka Watada

doi:10.1016/j.bbaexp.2006.01.004

Activin A-induced expression of PAX4 in AR42J-B13 cells involves the increase in transactivation of E47/E12

Rei Kanno, Takeshi Ogihara, Yasuhiro Igarashi, Yasushi Tanaka, Stuart B. Smith, Itaru Kojima, Michael S. German, Ryuzo Kawamori, Hirotaka Watada

Tohoku Medical Megabank Organization (ToMMo)

Research output: Contribution to journal › Article › peer-review

6 Citations (Scopus)

Abstract

Pax4 is a paired-homeodomain containing transcriptional factor that controls the differentiation of pancreatic β cells. The aim of this study was to investigate the mechanism of PAX4 expression by activin A. By reporter gene analysis using AR42J-B13 cells, in which treatment with activin A induced PAX4 mRNA expression, we identified that a short sequence located ∼1930 bp upstream of the transcriptional start site is essential for activin A induced PAX4 promoter activation. This region contains an E box and binding sites for hepatocyte nuclear factor (HNF)-1α. Mutation introduced in each binding site markedly reduced activin A responsiveness. It has been reported that HNF-1α synergizes with basic helix-loop-helix (bHLH) proteins in activating the PAX4 promoter, and we demonstrated that activin A strongly enhanced the functional activity of E47/E12 without the increase in its binding ability. In addition, suppression of E47/E12 expression in AR42J-B13 cells using siRNA oligonucleotides results in the significant decrease in the intrinsic activin A-induced PAX4 expression. Our results suggest that activin A enhances PAX4 expression by enhanced transactivation of E47/E12 proteins and might result in a cumulative transactivation of the promoter.

Original language	English
Pages (from-to)	44-50
Number of pages	7
Journal	Biochimica et Biophysica Acta - Gene Structure and Expression
Volume	1759
Issue number	1-2
DOIs	https://doi.org/10.1016/j.bbaexp.2006.01.004
Publication status	Published - 2006 Jan

Keywords

Gene regulation
Insulin
Pancreatic development
Pax4
Transcription factor
beta-cell

ASJC Scopus subject areas

Structural Biology
Biophysics
Biochemistry
Genetics

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Activin A-induced expression of PAX4 in AR42J-B13 cells involves the increase in transactivation of E47/E12. / Kanno, Rei; Ogihara, Takeshi; Igarashi, Yasuhiro; Tanaka, Yasushi; Smith, Stuart B.; Kojima, Itaru; German, Michael S.; Kawamori, Ryuzo; Watada, Hirotaka.

In: Biochimica et Biophysica Acta - Gene Structure and Expression, Vol. 1759, No. 1-2, 01.2006, p. 44-50.

Research output: Contribution to journal › Article › peer-review

Kanno, Rei ; Ogihara, Takeshi ; Igarashi, Yasuhiro ; Tanaka, Yasushi ; Smith, Stuart B. ; Kojima, Itaru ; German, Michael S. ; Kawamori, Ryuzo ; Watada, Hirotaka. / Activin A-induced expression of PAX4 in AR42J-B13 cells involves the increase in transactivation of E47/E12. In: Biochimica et Biophysica Acta - Gene Structure and Expression. 2006 ; Vol. 1759, No. 1-2. pp. 44-50.

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title = "Activin A-induced expression of PAX4 in AR42J-B13 cells involves the increase in transactivation of E47/E12",

abstract = "Pax4 is a paired-homeodomain containing transcriptional factor that controls the differentiation of pancreatic β cells. The aim of this study was to investigate the mechanism of PAX4 expression by activin A. By reporter gene analysis using AR42J-B13 cells, in which treatment with activin A induced PAX4 mRNA expression, we identified that a short sequence located ∼1930 bp upstream of the transcriptional start site is essential for activin A induced PAX4 promoter activation. This region contains an E box and binding sites for hepatocyte nuclear factor (HNF)-1α. Mutation introduced in each binding site markedly reduced activin A responsiveness. It has been reported that HNF-1α synergizes with basic helix-loop-helix (bHLH) proteins in activating the PAX4 promoter, and we demonstrated that activin A strongly enhanced the functional activity of E47/E12 without the increase in its binding ability. In addition, suppression of E47/E12 expression in AR42J-B13 cells using siRNA oligonucleotides results in the significant decrease in the intrinsic activin A-induced PAX4 expression. Our results suggest that activin A enhances PAX4 expression by enhanced transactivation of E47/E12 proteins and might result in a cumulative transactivation of the promoter.",

keywords = "Gene regulation, Insulin, Pancreatic development, Pax4, Transcription factor, beta-cell",

author = "Rei Kanno and Takeshi Ogihara and Yasuhiro Igarashi and Yasushi Tanaka and Smith, {Stuart B.} and Itaru Kojima and German, {Michael S.} and Ryuzo Kawamori and Hirotaka Watada",

note = "Funding Information: We thank Dr. Y. Eto (Ajinomoto Co., Japan) for kindly providing activin A and Naoko Daimaru and Yukiko Toyofuku for excellent technical assistance. This work was supported in part by grants from the Ministry of Education, Sports and Culture of Japan (to H. W.), and Kato Memorial Bioscience Foundation (to H. W.).",

year = "2006",

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AU - Kanno, Rei

AU - Ogihara, Takeshi

AU - Igarashi, Yasuhiro

AU - Tanaka, Yasushi

AU - Smith, Stuart B.

AU - Kojima, Itaru

AU - German, Michael S.

AU - Kawamori, Ryuzo

AU - Watada, Hirotaka

N1 - Funding Information: We thank Dr. Y. Eto (Ajinomoto Co., Japan) for kindly providing activin A and Naoko Daimaru and Yukiko Toyofuku for excellent technical assistance. This work was supported in part by grants from the Ministry of Education, Sports and Culture of Japan (to H. W.), and Kato Memorial Bioscience Foundation (to H. W.).

PY - 2006/1

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N2 - Pax4 is a paired-homeodomain containing transcriptional factor that controls the differentiation of pancreatic β cells. The aim of this study was to investigate the mechanism of PAX4 expression by activin A. By reporter gene analysis using AR42J-B13 cells, in which treatment with activin A induced PAX4 mRNA expression, we identified that a short sequence located ∼1930 bp upstream of the transcriptional start site is essential for activin A induced PAX4 promoter activation. This region contains an E box and binding sites for hepatocyte nuclear factor (HNF)-1α. Mutation introduced in each binding site markedly reduced activin A responsiveness. It has been reported that HNF-1α synergizes with basic helix-loop-helix (bHLH) proteins in activating the PAX4 promoter, and we demonstrated that activin A strongly enhanced the functional activity of E47/E12 without the increase in its binding ability. In addition, suppression of E47/E12 expression in AR42J-B13 cells using siRNA oligonucleotides results in the significant decrease in the intrinsic activin A-induced PAX4 expression. Our results suggest that activin A enhances PAX4 expression by enhanced transactivation of E47/E12 proteins and might result in a cumulative transactivation of the promoter.

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KW - Gene regulation

KW - Insulin

KW - Pancreatic development

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KW - Transcription factor

KW - beta-cell

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