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Background  Pancreas organogenesis is the result of well-orchestrated and balanced activities of transcription factors. The homeobox transcription factor PDX-1 plays a crucial role in the development and function of the pancreas, both in the maintenance of progenitor cells and in determination and maintenance of differentiated endocrine cells. However, the activity of homeobox transcription factors requires coordination with co-factors, such as PBX and MEIS proteins. PBX and MEIS proteins belong to the family of three amino acid loop extension (TALE) homeodomain proteins. In a previous study we found that PDX-1 negatively regulates the transcriptional activity of the ductal specific keratin 19 ( Krt19 ). In this study, we investigate the role of different domains of PDX-1 and elucidate the functional interplay of PDX-1 and MEIS1 necessary for  Krt19  regulation.    Methodology/Principal Findings  Here, we demonstrate that PDX-1 exerts a dual manner of regulation of  Krt19  transcriptional activity. Deletion studies highlight that the NH 2 -terminus of PDX-1 is functionally relevant for the down-regulation of  Krt19 , as it is required for DNA binding of PDX-1 to the  Krt19  promoter. Moreover, this effect occurs independently of PBX. Second, we provide insight on how PDX-1 regulates the Hox co-factor MEIS1 post-transcriptionally. We find specific binding of MEIS1 and MEIS2 to the  Krt19  promoter using IP-EMSA, and siRNA mediated silencing of  Meis1 , but not  Meis2 , reduces transcriptional activation of  Krt19  in primary pancreatic ductal cells. Over-expression of PDX-1 leads to a decreased level of MEIS1 protein, and this decrease is prevented by inhibition of the proteasome.    Conclusions/Significance  Taken together, our data provide evidence for a dual mechanism of how PDX-1 negatively regulates  Krt19  ductal specific gene expression. These findings imply that transcription factors may efficiently regulate target gene expression through diverse, non-redundant mechanisms.

The Pancreatic and Duodenal Homeobox Protein PDX-1 Regulates the Ductal Specific Keratin 19 through the Degradation of MEIS1 and DNA Binding