Pbx1 is a co-factor for Cdx-2 in regulating proglucagon gene expression in pancreatic A cells.
A number of Hox and Hox-like homeodomain (HD) proteins have been previously shown to utilize members of the TALE HD protein family as co-factors in regulating gene expression. The caudal HD protein Cdx-2 is a transactivator for the proglucagon gene, expressed in pancreatic A cells and intestinal endocrine L cells. We demonstrate here that co-transfection of the TALE homeobox gene Pbx1 enhanced the activation of Cdx-2 on the proglucagon promoter in either the pancreatic A cell line InR1-G9 or BHK fibroblasts. The activation was observed for proglucagon promoter constructs with or without the binding motifs for Pbx1. Furthermore, mutating the penta-peptide motif (binding motif for TALE HD proteins) on Cdx-2 substantially attenuated its activation on proglucagon promoter, but not on the sucrase-isomaltase gene (SI) promoter, or its own (Cdx-2) promoter; suggesting that Cdx-2 utilizes Pbx1 as a co-factor for regulating the expression of selected target genes. Physical interaction between Cdx-2 and Pbx1 was demonstrated by co-immunoprecipitation as well as GST fusion protein pull-down. We suggest that this study reveals a novel function for Pbx1 in pancreatic islet physiology: regulating proglucagon expression by serving as a co-factor for Cdx-2.
Department of Medicine and Institute of Medical Science, University of Toronto, Rm. 410, 67 College Street, Toronto, Ont., Canada M5G 2M1.
Tao
T
Liu
Donald R
DR
Branch
Tianru
T
Jin
D020816:Amino Acid Motifs; D000818:Animals; D000071616:CDX2 Transcription Factor; D002460:Cell Line; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation; D050416:Glucagon-Secreting Cells / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D052336:Proglucagon / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D025941:Protein Interaction Mapping; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*
D000071616:CDX2 Transcription Factor; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; C083400:PBX1 protein, human; D052336:Proglucagon