Identification of a Portable Repression Domain and an E1A-Responsive Activation Domain in Pax4: a Possible Role of Pax4 as a Transcriptional Repressor in the Pancreas

Fujitani, Yoshio; Kajimoto, Yoshitaka; Yasuda, Tetsuyuki; Matsuoka, Taka‐aki; Kaneto, Hideaki; Umayahara, Yutaka; Fujita, Noriko; Watada, Hirotaka; Miyazaki, Junichi; Yamasaki, Yoshimitsu; Hori, Masatsugu

doi:10.1128/mcb.19.12.8281

Cited by 64 publications

(76 citation statements)

References 61 publications

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“…The Cterminal domain missing in ilr3-1 does not contain recognizable motifs, but is conserved in other members of the ILR3 bHLH subgroup (Heim et al 2003), including those in rice (Figure 2A). Other bHLH proteins have similarly positioned transcriptional activation (Franks and Crews 1994;Gerber et al 1997;Ema et al 1999) or repression domains (Sato et al 1994;Fisher et al 1996;Fujitani et al 1999). As the bHLH and leucine zipper domains remain intact in ilr3-1, it is tempting to speculate that the ilr3-1 protein still dimerizes and binds DNA via the intact bHLH and leucine zipper domains, but the missing C-terminal domain prevents proper modulation of gene expression.…”

Section: Resultsmentioning

confidence: 99%

An Arabidopsis Basic Helix-Loop-Helix Leucine Zipper Protein Modulates Metal Homeostasis and Auxin Conjugate Responsiveness

et al. 2006

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The plant hormone auxin can be regulated by formation and hydrolysis of amide-linked indole-3-acetic acid (IAA) conjugates. Here, we report the characterization of the dominant Arabidopsis iaa-leucine resistant3 (ilr3-1) mutant, which has reduced sensitivity to IAA-Leu and IAA-Phe, while retaining wild-type responses to free IAA. The gene defective in ilr3-1 encodes a basic helix-loop-helix leucine zipper protein, bHLH105, and the ilr3-1 lesion results in a truncated product. Overexpressing ilr3-1 in wild-type plants recapitulates certain ilr3-1 mutant phenotypes. In contrast, the loss-of-function ilr3-2 allele has increased IAA-Leu sensitivity compared to wild type, indicating that the ilr3-1 allele confers a gain of function. Microarray and quantitative real-time PCR analyses revealed five downregulated genes in ilr3-1, including three encoding putative membrane proteins similar to the yeast iron and manganese transporter Ccc1p. Transcript changes are accompanied by reciprocally misregulated metal accumulation in ilr3-1 and ilr3-2 mutants. Further, ilr3-1 seedlings are less sensitive than wild type to manganese, and auxin conjugate response phenotypes are dependent on exogenous metal concentration in ilr3 mutants. These data suggest a model in which the ILR3/bHLH105 transcription factor regulates expression of metal transporter genes, perhaps indirectly modulating IAA-conjugate hydrolysis by controlling the availability of metals previously shown to influence IAA-amino acid hydrolase protein activity.

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Section: Resultsmentioning

confidence: 99%

An Arabidopsis Basic Helix-Loop-Helix Leucine Zipper Protein Modulates Metal Homeostasis and Auxin Conjugate Responsiveness

et al. 2006

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“…Its relative activity is, however, more than twofold lower than Pax-6 TAD and inactive in pancreatic islet-cell lines [23,37]. Moreover, repression domains have been mapped to the Pax-4 HD and C-terminal region [22,23,27] but no cofactors mediating this effect have as yet been identified.…”

Section: Discussionmentioning

confidence: 99%

“…Pax-4 has been shown to act as a DNA binding dependent transcriptional repressor in a Gal4 system [22,23] and inhibits several islet specific promoters such as the glucagon, insulin and islet amyloid polypeptide (IAPP), and its own promoter in transient transfection studies [22, 24±27]. Pax-4 might therefore be implicated in a-cell-specific expression of the glucagon gene by suppressing glucagon gene transcription in differentiating insulin-producing cells.…”

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confidence: 99%

The pancreatic beta-cell-specific transcription factor Pax-4 inhibits glucagon gene expression through Pax-6

et al. 2002

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The endocrine pancreas is organised as islets of Langerhans embedded in the exocrine tissue and is composed of four cell types: beta, a, d, and g cells producing insulin, glucagon, somatostatin and the pancreatic polypeptide (PP), respectively. Gene knockout studies have shown the involvement of a variety of transcription factors in pancreas development. Null mutations of the homeodomain proteins pdx-1 and isl-1 result in pancreatic agenesis and the absence of the islets of Langerhans, respectively [1,2]. The lack of Beta2, Pax-6, Pax-4, Nk 2.2, and Nk 6.1 affects the organisation of the endocrine pancreas and the number of endocrine cells or both [3±9]. The formation of specific islet cell types can be affected by the absence of any of these factors: no or few glucagon-producing a cells are observed in homozygous pax-6 mutants, whereas pax-4 knockout mice lack beta and d cells; nk 2.2 and nk 6.1 mu-The pancreatic beta-cell-specific transcription factor Pax-4 inhibits glucagon gene expression through Pax-6 Abstract Aims/hypothesis. The paired-homeobox genes pax-4 and pax-6 are crucial for islet development; whereas the null mutation of pax-6 results in the nearly absence of glucagon-producing a cells, pax-4 homozygous mutant mice lack insulin and somatostatin-producing beta and d cells but contain an increased number of a cells suggesting that a cells could develop by a default mechanism. Methods. To investigate whether beta-cell specific factors act negatively on glucagon gene transcription, we ectopically expressed pax-4 in glucagon producing InR1G9 cells; Pax-4 inhibited basal transcription of the glucagon gene promoter by 60 %. To assess the mechanism of this inhibition, we cotransfected the non-islet cell line BHK-21 with Pax-4 and various transcription factors present in a cells.Results. In addition to a general repressor activity on basal glucagon gene promoter activity of 30±50 %, a specific 90 % inhibition of Pax-6 mediated transactivation was observed. In contrast, Pax-4 had no effect on Cdx-2/3 or HNF3a mediated transcriptional activation. Pax-4 showed similar affinity to the Pax-6 binding sites on the glucagon gene promoter compared to Pax-6, but varying with KCl concentrations. Conclusion/interpretation. Pax-4 impairs glucagon gene transcription specifically through inhibition of Pax-6 mediated transactivation. Transcriptional inhibition seems to be mediated by direct DNA binding competition with Pax-6 and potentially additional mechanisms such as protein-protein interactions and a general repressor activity of Pax-4. Glucagon gene expression in a cells could thus result from both the presence of islet cell specific transcription factors and the absence of Pax-4. [Diabetologia (2002) 45: 97±107]

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“…In contrast to many target genes of Pa 6, the target genes of Pa 4 have not yet been found in spite of an extensive search. Recently, it was reported that DNA binding specificities of Pa 4 and Pa 6 are similar and Pa 4 can act as a Pa 6 repressor by the competition for binding sites [25,26]. Possibly Pa 4 inhibits the induction of the alpha-cell phenotype by Pa 6 in normal beta cells.…”

Section: Discussionmentioning

confidence: 99%

Diabetes and pancreatic tumours in transgenic mice expressing Pa × 6

et al. 2000

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Identification of a Portable Repression Domain and an E1A-Responsive Activation Domain in Pax4: a Possible Role of Pax4 as a Transcriptional Repressor in the Pancreas

Abstract: Pax4 is a paired-domain (PD)-

Cited by 64 publications

References 61 publications

An Arabidopsis Basic Helix-Loop-Helix Leucine Zipper Protein Modulates Metal Homeostasis and Auxin Conjugate Responsiveness

An Arabidopsis Basic Helix-Loop-Helix Leucine Zipper Protein Modulates Metal Homeostasis and Auxin Conjugate Responsiveness

The pancreatic beta-cell-specific transcription factor Pax-4 inhibits glucagon gene expression through Pax-6

Diabetes and pancreatic tumours in transgenic mice expressing Pa × 6

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