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 interactio n can increase the binding specificity and transcriptional effectivene ss of the HOX partner. Here we show that specific members of both PBX and MEIS subclasses form a multimeric complex with the pancreatic home odomain protein PDX1 and switch the nature of its transcriptional acti vity. The two activities of PDX1 are exhibited through the 10-bp B ele ment of the transcriptional enhancer of the pancreatic elastase I gene (ELA1). In pancreatic acinar cells the activity of the B element requ ires 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 PDX 1, PBX1b, and MRG1 (MEIS2). In contrast, beta-cell lines are devoid of PBX2b and MRG1, so that a trimeric complex does not form, and the bet a-cell-type activity is mediated by PDX1 without PBX1b and MRGI, The p resence of specific nuclear isoforms of PBX and MEIS is precisely regu lated 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 bind ing of PDX1 but prevent binding of the PDX1-PBX1b-MRG1 complex. These observations suggest that association with PBX and MEIS partners contr ols the nature of the transcriptional activity of the organ-specific P DX1 transcription factor in exocrine versus endocrine cells.