Role of Deltex-1 as a transcriptional regulator downstream of the Notch receptor.
Intercellular signaling through the cell-surface receptor Notch plays important roles in a variety of developmental processes as well as in pathogenesis of some human cancers and genetic disorders. However, the mechanisms by which Notch signals are transduced into cells still remain elusive. Here we investigated the signaling mechanisms for Notch in the cell fate control of neural progenitor cells. We show that Deltex-1 (DTX1), a mammalian homolog of Drosophila Deltex, mediates a Notch signal to block differentiation of neural progenitor cells. We found that a significant fraction of DTX1 proteins were localized in the nucleus and physically interacted with the transcriptional coactivator p300. Through its binding to p300, DTX1 inhibited transcriptional activation by the neural-specific helix-loop-helix-type transcription factor MASH1, and this mechanism is likely responsible for the differentiation inhibition of neural progenitor cells. Our results further suggest that DTX1 regulates transcription independently of the previously characterized Notch signaling pathway involving RBP-J and HES1/HES5. Thus, DTX1 serves as an important signaling component downstream of Notch that regulates transcription in the nucleus.
Yamamoto
N
N
Department of Neurobiology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
Yamamoto
S
S
Inagaki
F
F
Kawaichi
M
M
Fukamizu
A
A
Kishi
N
N
Matsuno
K
K
Nakamura
K
K
Weinmaster
G
G
Okano
H
H
Nakafuku
M
M
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D015153:Blotting, Western; D019556:COS Cells; D002352:Carrier Proteins; D002454:Cell Differentiation; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D029721:Drosophila Proteins; D004331:Drosophila melanogaster; D050881:E1A-Associated p300 Protein; D017353:Gene Deletion; D017930:Genes, Reporter; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000378:metabolism* / Q000502:physiology*; D051379:Mice; D016296:Mutagenesis; D009687:Nuclear Proteins / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism* / Q000502:physiology*; D051381:Rats; D051880:Receptors, Notch; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection
D051792:Basic Helix-Loop-Helix Proteins; D002352:Carrier Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D050881:E1A-Associated p300 Protein; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011506:Proteins; D051880:Receptors, Notch; D015534:Trans-Activators; D014157:Transcription Factors; C065500:ASCL1 protein, human; C499317:Ascl1 protein, mouse; C499318:Ascl1 protein, rat; C497759:N protein, Drosophila; C409218:deltex protein, vertebrate; C494361:Ep300 protein, mouse; C494362:Ep300 protein, rat