{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T15:16:10Z","timestamp":1791645370800,"version":"4.3.4"},"reference-count":74,"publisher":"Cold Spring Harbor Laboratory","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes Dev."],"published-print":{"date-parts":[[1995,4,15]]},"abstract":"<jats:p>The insulin gene is one of the best paradigms of tissue-specific gene expression. It is developmentally regulated and is expressed exclusively in the pancreatic beta-cell. This restricted expression is directed by a tissue-specific enhancer, within the promoter, which contains an E-box sequence. The insulin E-box binds an islet-specific protein complex, termed 3a1. E-boxes bind proteins belonging to the basic helix-loop-helix (bHLH) family of transcription factors. The bHLH proteins function as potent transcriptional activators of tissue-specific genes by forming heterodimers between ubiquitous and cell-restricted family members. In addition, the cell-restricted bHLH members play an important role in specifying cell fate. To isolate the tissue-specific bHLH factor controlling insulin gene expression and study its role in islet cell differentiation, a modified yeast two-hybrid system was utilized to clone a novel bHLH factor, BETA2 (beta-cell E-box trans-activator 2), from a hamster insulin tumor (HIT) cell cDNA library. Northern analysis demonstrates that high-level expression of the BETA2 gene is restricted to pancreatic alpha- and beta-cell lines. As expected of tissue-specific bHLH members, BETA2 binds to the insulin E-box sequence with high affinity as a heterodimer with the ubiquitous bHLH factor E47. More importantly, antibody supershift experiments clearly show that BETA2 is a component of the native insulin E-box-binding complex. Transient transfection assays demonstrate that the BETA2\/E47 heterodimer synergistically interacts with a neighboring beta-cell-specific complex to activate an insulin enhancer. In contrast, other bHLH factors such as MyoD and E47, which can bind to the insulin E-box with high affinity, fail to do so. Thus, a unique, cooperative interaction is the basis by which the insulin E-box enhancer discriminates between various bHLH factors to achieve tissue-specific activation of the insulin gene.<\/jats:p>","DOI":"10.1101\/gad.9.8.1009","type":"journal-article","created":{"date-parts":[[2007,6,5]],"date-time":"2007-06-05T21:15:46Z","timestamp":1181078146000},"page":"1009-1019","source":"Crossref","is-referenced-by-count":487,"title":["Tissue-specific regulation of the insulin gene by a novel basic helix-loop-helix transcription factor."],"prefix":"10.1101","volume":"9","author":[{"given":"F J","family":"Naya","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C M","family":"Stellrecht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M J","family":"Tsai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"246","published-online":{"date-parts":[[1995,4,15]]},"reference":[{"key":"2021111418220615000_9.8.1009.1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(88)90391-1"},{"key":"2021111418220615000_9.8.1009.2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/19.14.3893"},{"key":"2021111418220615000_9.8.1009.3","doi-asserted-by":"publisher","DOI":"10.1101\/gad.5.6.1057"},{"key":"2021111418220615000_9.8.1009.4","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.86.24.10128"},{"key":"2021111418220615000_9.8.1009.5","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(90)90214-Y"},{"key":"2021111418220615000_9.8.1009.6","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(88)90250-4"},{"key":"2021111418220615000_9.8.1009.7","first-page":"1734","article-title":"Pancreatic \u03b2-cell-type-specific transcription of the insulin gene is mediated by basic helix-loop-helix DNA-binding proteins.","volume":"11","year":"1991","journal-title":"Mol. 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