An endocrine-exocrine switch in the activity of the pancreatic homeodomain protein PDX1 through formation of a trimeric complex with PBX1b and MRG1 (MEIS2).
HOX proteins and some orphan homeodomain proteins form complexes with either PBX or MEIS subclasses of homeodomain proteins. This interaction can increase the binding specificity and transcriptional effectiveness of the HOX partner. Here we show that specific members of both PBX and MEIS subclasses form a multimeric complex with the pancreatic homeodomain protein PDX1 and switch the nature of its transcriptional activity. The two activities of PDX1 are exhibited through the 10-bp B element of the transcriptional enhancer of the pancreatic elastase I gene (ELA1). In pancreatic acinar cells the activity of the B element requires other elements of the ELA1 enhancer; in beta-cells the B element can activate a promoter in the absence of other enhancer elements. In acinar cell lines the activity is mediated by a complex comprising PDX1, PBX1b, and MRG1 (MEIS2). In contrast, beta-cell lines are devoid of PBX1b and MRG1, so that a trimeric complex does not form, and the beta-cell-type activity is mediated by PDX1 without PBX1b and MRG1. The presence of specific nuclear isoforms of PBX and MEIS is precisely regulated in a cell-type-specific manner. The beta-cell-type activity can be detected in acinar cells if the B element is altered to retain binding of PDX1 but prevent binding of the PDX1-PBX1b-MRG1 complex. These observations suggest that association with PBX and MEIS partners controls the nature of the transcriptional activity of the organ-specific PDX1 transcription factor in exocrine versus endocrine cells.
Department of Molecular Biology and Oncology, University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA. swift@hamon.swmed.edu
G H
GH
Swift
Y
Y
Liu
S D
SD
Rose
L J
LJ
Bischof
S
S
Steelman
A M
AM
Buchberg
C V
CV
Wright
R J
RJ
MacDonald
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000302:isolation & purification / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D015723:Gene Library; D005914:Globins / Q000096:biosynthesis; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000378:metabolism*; D019382:Human Growth Hormone / Q000096:biosynthesis; D006801:Humans; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D010179:Pancreas / Q000166:cytology / Q000378:metabolism*; D010196:Pancreatic Elastase / Q000096:biosynthesis* / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000378:metabolism; D012097:Repressor Proteins; D015534:Trans-Activators / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014982:Xenopus laevis
C486381:CITED2 protein, human; C110087:Cited2 protein, mouse; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D019382:Human Growth Hormone; D005914:Globins; D010196:Pancreatic Elastase