Mammalian Scratch: a neural-specific Snail family transcriptional repressor.
Members of the Snail family of zinc finger transcription factors are known to play critical roles in neurogenesis in invertebrates, but none of these factors has been linked to vertebrate neuronal differentiation. We report the isolation of a gene encoding a mammalian Snail family member that is restricted to the nervous system. Human and murine Scratch (Scrt) share 81% and 69% identity to Drosophila Scrt and the Caenorhabditis elegans neuronal antiapoptotic protein, CES-1, respectively, across the five zinc finger domain. Expression of mammalian Scrt is predominantly confined to the brain and spinal cord, appearing in newly differentiating, postmitotic neurons and persisting into postnatal life. Additional expression is seen in the retina and, significantly, in neuroendocrine (NE) cells of the lung. In a parallel fashion, we detect hScrt expression in lung cancers with NE features, especially small cell lung cancer. hScrt shares the capacity of other Snail family members to bind to E-box enhancer motifs, which are targets of basic helix--loop--helix (bHLH) transcription factors. We show that hScrt directly antagonizes the function of heterodimers of the proneural bHLH protein achaete-scute homolog-1 and E12, leading to active transcriptional repression at E-box motifs. Thus, Scrt has the potential to function in newly differentiating, postmitotic neurons and in cancers with NE features by modulating the action of bHLH transcription factors critical for neuronal differentiation.
Nakakura
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EK
Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Watkins
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DN
Schuebel
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KE
Sriuranpong
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V
Borges
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MW
Nelkin
B D
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Ball
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D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D016384:Consensus Sequence / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004330:Drosophila; D029721:Drosophila Proteins; D020868:Gene Silencing; D017930:Genes, Reporter; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism*; D009490:Neurosecretory Systems / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000302:isolation & purification*; D017386:Sequence Homology, Amino Acid; D012908:Snails / Q000235:genetics; D051820:TCF Transcription Factors; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors / Q000235:genetics / Q000302:isolation & purification*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D012097:Repressor Proteins; D051820:TCF Transcription Factors; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors; C065500:ASCL1 protein, human; C499317:Ascl1 protein, mouse; C544912:TCF7L1 protein, human; C544913:Tcf7l1 protein, mouse; C096141:scrt protein, Drosophila