Abstract
In keratinocytes, the cyclin/CDK inhibitor p21(WAF1/Cip1) is a direct transcriptional target of Notch1 activation; loss of either the p21 or Notch1 genes expands stem cell populations and facilitates tumor development. The Notch1 tumor-suppressor function was associated with down-regulation of Wnt signaling. Here, we show that suppression of Wnt signaling by Notch1 activation is mediated, at least in part, by down-modulation of Wnts gene expression. p21 is a negative regulator of Wnts transcription downstream of Notch1 activation, independently of effects on the cell cycle. More specifically, expression of the Wnt4 gene is under negative control of endogenous p21 both in vitro and in vivo. p21 associates with the E2F-1 transcription factor at the Wnt4 promoter and causes curtailed recruitment of c-Myc and p300, and histone hypoacetylation at this promoter. Thus, p21 acts as a selective negative regulator of transcription and links the Notch and Wnt signaling pathways in keratinocyte growth control.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Basic Helix-Loop-Helix Transcription Factors
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Cell Cycle
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cell Differentiation
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Cell Division
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Cells, Cultured
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Cyclin-Dependent Kinase Inhibitor p21
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DNA-Binding Proteins / metabolism
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Down-Regulation
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E1A-Associated p300 Protein
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E2F Transcription Factors
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E2F1 Transcription Factor
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Keratinocytes / cytology
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Keratinocytes / metabolism
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Mice
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Mice, Knockout
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Nuclear Proteins / metabolism
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Promoter Regions, Genetic
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins c-myc / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptor, Notch1
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / metabolism*
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Signal Transduction
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Trans-Activators / metabolism
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Transcription Factor HES-1
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcription, Genetic
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Wnt Proteins
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Wnt4 Protein
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Cdkn1a protein, mouse
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p21
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DNA-Binding Proteins
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E2F Transcription Factors
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E2F1 Transcription Factor
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E2f1 protein, mouse
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Hes1 protein, mouse
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Homeodomain Proteins
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Myc protein, mouse
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Notch1 protein, mouse
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Nuclear Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-myc
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RNA, Messenger
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Receptor, Notch1
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Receptors, Cell Surface
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Trans-Activators
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Transcription Factor HES-1
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Transcription Factors
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Wnt Proteins
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Wnt4 Protein
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Wnt4 protein, mouse
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E1A-Associated p300 Protein
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Ep300 protein, mouse