The pancreatic islet factor STF-1 binds cooperatively with Pbx to a regulatory element in the somatostatin promoter: importance of the FPWMK motif and of the homeodomain.
A number of homeodomain proteins have been shown to regulate cellular development by stimulating the transcription of specific target genes. In contrast to their distinct activities in vivo, however, most homeodomain proteins bind indiscriminately to potential target sites in vitro, suggesting the involvement of cofactors which specify target site selection. One such cofactor, termed extradenticle, has been shown to influence segmental morphogenesis in Drosophila melanogaster by binding cooperatively with certain homeodomain proteins to target regulatory elements. Here we demonstrate that STF-1, an orphan homeodomain protein required for pancreatic development in mammals, binds cooperatively to DNA with Pbx, the mammalian homolog of extradenticle. Cooperative binding with Pbx requires a pentapeptide motif (FPWMK) which is well conserved among a large subset of homeodomain proteins. The FPMWK motif is not sufficient to confer Pbx cooperativity on other homeodomain proteins, however; the N-terminal arm of the STF-1 homeodomain is also essential. As cooperative binding with Pbx occurs on only a subset of potential STF-1 target sites, our results suggest that Pbx may specify target gene selection in the developing pancreas by forming heterodimeric complexes with STF-1.
Clayton Foundation Laboratories for Peptide Biology, Salk Institute, La Jolla, California 92037, USA.
B
B
Peers
S
S
Sharma
T
T
Johnson
M
M
Kamps
M
M
Montminy
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000502:physiology; D005801:Genes, Homeobox; D018398:Homeodomain Proteins / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism*; D008969:Molecular Sequence Data; D009024:Morphogenesis; D009838:Oligodeoxyribonucleotides; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D017384:Sequence Deletion; D013004:Somatostatin / Q000096:biosynthesis / Q000235:genetics*; D013379:Substrate Specificity; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D009838:Oligodeoxyribonucleotides; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; C083400:PBX1 protein, human; D013004:Somatostatin