DNA Binding and Transactivating Properties of the Paired and Homeobox Protein Pax4

Kalousova, Anna; Beneš, Vladimı́r; Pačes, Jan; Pačes, Václav; Kozmík, Zbyněk

doi:10.1006/bbrc.1999.0809

Cited by 25 publications

(22 citation statements)

References 41 publications

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“…Indeed, the exogenous expression of E1A in a heterologous cell line (CHO-K1) could convert the activation domain into an active one, whereas it did not affect the function of the repression domain (Table 3). During revision of this report, Kalousová et al reported that whereas Pax4 and Pax6 have similar DNAbinding specificities, the Pax4 C-terminal region can activate the GAL4 reporter 2.5-fold less than the comparable region of Pax6 (23). Their experiments used 293 cells, and the relative potency of transactivation by Pax4 to that by Pax6 was consistent with the data that we obtained for 293T cells (Fig.…”

Section: Discussionsupporting

confidence: 90%

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

Fujitani¹,

Kajimoto²,

Yasuda³

et al. 1999

Molecular and Cellular Biology

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Section: Discussionsupporting

confidence: 90%

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

Fujitani¹,

Kajimoto²,

Yasuda³

et al. 1999

Molecular and Cellular Biology

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“…In support of this theory, our analysis of approximately 2 kb of mouse ghrelin upstream sequences revealed two motifs resembling consensus Pax4/Pax6-binding sites located approximately 1.32 kb and 0.45 kb upstream of the ATG translation initiation codon ( Fig. 5A,B ;Fujitani et al, 1999;Kaulosova et al, 1999;Smith et al, 1999). To investigate whether Pax4 represses ghrelin gene expression, we performed various biochemical analyses on cells maintained in culture.…”

Section: Pax4 Directly Represses Ghrelin Gene Expressionmentioning

confidence: 60%

“…Therefore, identifying potential targets of Pax4 is a necessary step toward learning how this transcription factor controls early endocrine development in the pancreas. Previous studies have shown that, in certain cellular contexts, Pax4 directly represses the expression of various islet genes, including glucagon, Arx, islet amyloid polypeptide (IAPP), and insulin (Campbell et al, 1999;Fujitani, et al, 1999;Kaulosova, et al, 1999;Smith, et al, 1999;Petersen, et al, 2000;Ritz-Laser et al, 2002;Collombat et al, 2005). Consequently, it has been proposed that, in developing endocrine cells of the pancreas, Pax4 functions primarily as a transcriptional repressor (Fujitani et al, 1999;Smith et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

ghrelinis a novel target of Pax4 in endocrine progenitors of the pancreas and duodenum

Wang

Elghazi

Martin

et al. 2007

Developmental Dynamics

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Pax4-deficient mice have a severe gastrointestinal endocrine deficiency: they lack most pancreatic cells that produce insulin or somatostatin and various duodenal endocrine cell types. Remarkably, Pax4-deficient mice also have an overabundance of ghrelin-expressing cells in the pancreas and duodenum. Detailed analysis of the Pax4 nullizygous pancreas determined that the mutant islets are largely composed of a distinctive endocrine cell type that expresses ghrelin, glucagon, islet amyloid polypeptide (IAPP), and low levels of Pdx1. Lineage-tracing analysis revealed that most of these unique endocrine cells directly arose from Pax4-deficient progenitors. Previous in vitro work reported that Pax4 is a transcriptional repressor of islet amyloid polypeptide (IAPP) and glucagon. In this study, we expanded those results by showing that Pax4 is also a repressor of gherlin. Together, our data further support the notion that Pax4 activity is necessary to establish appropriate patterns of gene expression in endocrine progenitors of the digestive tract. Developmental Dynamics 237:51-61, 2008.

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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%

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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DNA Binding and Transactivating Properties of the Paired and Homeobox Protein Pax4

Cited by 25 publications

References 41 publications

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

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

ghrelinis a novel target of Pax4 in endocrine progenitors of the pancreas and duodenum

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

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