Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alx3 is a paired class aristaless-like homeoprotein expressed during embryonic development. Transcriptional transactivation by aristaless-like proteins has been associated with cooperative dimerization upon binding to artificially generated DNA consensus sequences known as P3 sites, but natural target sites in genes regulated by Alx3 are unknown. We report the cloning of a cDNA encoding the rat homolog of Alx3, and we characterize the protein domains that are important for transactivation, dimerization, and binding to DNA. Two proline-rich domains located amino-terminal to the homeodomain (Pro1 and Pro2) are necessary for Alx3-dependent transactivation, whereas another one (Pro3) located in the carboxyl terminus is dispensable but contributes to enhance the magnitude of the response. We confirmed that transcriptional activity of Alx3 from a P3 site correlates with cooperative dimerization upon binding to DNA. However, Alx3 was found to bind selectively to non-P3-related TAAT-containing sites present in the promoter of the somatostatin gene in a specific manner that depends on the nuclear protein environment. Cell-specific transactivation elicited by Alx3 from these sites could not be predicted from in vitro DNA-binding experiments by using recombinant Alx3. In addition, transactivation did not depend on cooperative dimerization upon binding to cognate somatostatin DNA sites. Our data indicate that the paradigm according to which Alx3 must act homodimerically via cooperative binding to P3-like sites is insufficient to explain the mechanism of action of this homeoprotein to regulate transcription of natural target genes. Instead, Alx3 undergoes restrictive or permissive interactions with nuclear proteins that determine its binding to and transactivation from TAAT target sites selected in a cell-specific manner.
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PMID:The homeoprotein Alx3 contains discrete functional domains and exhibits cell-specific and selective monomeric binding and transactivation. 1522 5

The regulation of insulin gene expression in pancreatic beta-cells is the result of the coordinate activity of specific combinations of transcription factors assembled on different promoter elements. We investigated the involvement of the aristaless-related homeoprotein Alx3 in this process. We found that Alx3 is coexpressed with insulin in pancreatic islets, as well as in the beta-cell line MIN6, and it is also present in glucagon- and somatostatin-expressing cells. Chromatin immunoprecipitation assays indicated that Alx3 present in MIN6 cells and in mouse pancreatic islets occupies the promoter of the mouse insulin genes. EMSAs indicated that Alx3 present in MIN6 cells binds to the A3/4 regulatory element of the insulin I promoter. We found that Alx3 transactivates the insulin promoter by acting on the E2A3/4 enhancer in conjunction with the basic helix-loop-helix transcription factors E47/Pan1 and Beta2/NeuroD, and that Alx3 physically interacts via the homeodomain with E47/Pan1 but not with Beta2/NeuroD. Alx3 binds to the A3/4 element as a dimer, and the homeodomain is sufficient to recruit E47/Pan1 to the insulin promoter. Deletion studies in transfected HeLa cells indicated that proline-rich regions located at either side of the Alx3 homeodomain work together with E47/Pan1, and that this requires the integrity of the amino-terminal activation domain to transactivate. Thus, these studies support the notion that Alx3 participates in the regulation of insulin gene expression in pancreatic beta-cells.
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PMID:The homeoprotein Alx3 expressed in pancreatic beta-cells regulates insulin gene transcription by interacting with the basic helix-loop-helix protein E47. 1682 92