The Paired Homeodomain Transcription Factor Pax-2 Is Expressed in the Endocrine Pancreas and Transactivates the Glucagon Gene Promoter

Abstract

Glucagon gene expression is controlled by at least four DNA elements within the promoter; G2, G3, and G4 confer islet-specific expression, while G1 restricts glucagon transcription to ␣ cells. Two islet-specific complexes are formed on G3, the insulin-responsive element of the glucagon gene; one of these corresponds to the paired homeodomain protein Pax-6, a major glucagon gene transactivator that plays a crucial role in ␣ cell development. We describe here the identification of the second complex as Pax-2, another member of the paired box family. Pax-2 is known to be crucial for the development of the urogenital tract and of the central nervous system, but its presence in the endocrine pancreas has not been reported. We detected Pax-2 gene expression by RT-PCR; in islets, Pax-2 is present as two alternative splicing isoforms, Pax-2A and Pax-2B, whereas in the glucagon-and insulin-producing cell lines ␣TC1 and Min6, a distinct isoform, Pax-2D2, is found in addition to Pax-2B. Both islet-specific isoforms bind to the enhancer element G3 and to the ␣-specific promoter element G1 that also interacts with Pax-6. Pax-2A and Pax-2B dose-dependently activate transcription from the G3 and the G1 elements both in heterologous and in glucagon-producing cells. Our data indicate that Pax-2 is the third paired domain protein present in the endocrine pancreas and that one of its roles may be the regulation of glucagon gene expression.

Interaction of Maf Transcription Factors with Pax-6 Results in Synergistic Activation of the Glucagon Promoter

“…We tested the effect of the simultaneous expression of Pax-2 and MafA on the G3-138 glucagon promoter. The D2 form of Pax-2 (a splicing variant in the transactivation domain) was a better transactivator than Pax-6, whereas the C form (36) exhibited only a marginal effect on glucagon expression (Fig. 3A).…”

“…Another Pax family member (Pax-2) has been described to activate the glucagon promoter through the G1 element (36). We tested the effect of the simultaneous expression of Pax-2 and MafA on the G3-138 glucagon promoter.…”

PAX8 expression reliably distinguishes pancreatic well-differentiated neuroendocrine tumors from ileal and pulmonary well-differentiated neuroendocrine tumors and pancreatic acinar cell carcinoma

“…14,15 In particular, PAX4 and PAX6 are essential for development of pancreatic islet cells as well as endocrine cell development in the small intestine and stomach. [14][15][16] Although PAX8 has been most studied in renal tissues and neoplasms, 17 it has been recently recognized as a useful marker in distinguishing ovarian from breast carcinoma, 18 and as a marker of thyroid epithelial neoplasms. 19 Moreover, our group recently observed intense PAX8 reactivity in pancreatic neuroendocrine tumors and normal pancreatic islets in a large tissue microarray evaluation of PAX8 immunoreactivity of non-renal tissues/neoplasms.…”

Multicystic Dysplastic Kidney and Variable Phenotype in a Family with a Novel Deletion Mutation of PAX2

“…PAX2 encodes a transcription factor that belongs to the "paired-box" family of homeotic genes. During embryogenic development, it is abundantly expressed in the kidney, eye, cochlear (14), pancreas (15), and central nervous system (11,16,17) and is involved in the regulation of several genes, such as WT1 (18), N-myc (19), and p53 (19).…”