p21WAF1/Cip1 is a negative transcriptional regulator of Wnt4 expression downstream of Notch1 activation
Open accessAbstract
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.
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In mouse keratinocytes, p21 inhibits Wnt4 expression by binding to the TATA-proximal region of the Wnt4 promoter in association with E2F-1.
“In mouse keratinocytes, p21 inhibits Wnt4 expression by binding to the TATA-proximal region of the Wnt4 promoter in association with E2F transcription factor 1 (E2F-1)24, and levels of p21 expression were negatively correlated with Wnt4 expression in our RNA-seq analysis (Fig. 6b).”
From In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche (2021) · cites this paper as [24]
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References 43 · Cited by 209
Research works printed but not linked: 1
- Chang, B.D., Watanabe, K., Broude, E.V., Fang, J., Poole, J.C., Kalinichenko, T.V., and Roninson, I.B. 2000. Effects of p21Waf1/Cip1/Sdi1 on cellular gene expression: Implica- tions for carcinogenesis, senescence, and age-related dis- eases. Proc. Natl. Acad. Sci. 97: 4291-4296.
- Authors
- Devgan, V., Mammucari, C., Millar, S. E., Brisken, C., & Dotto, G. P.
- Affiliations
- Massachusetts General Hospital (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2005-06-15
- Volume
- 19
- Issue
- 12
- Pages
- 1485-1495
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC1151665
- OpenAlex
- W2118109822
- Cited by
- 209
- References
- 43
- Citations by year
- 2025: 3 · 2024: 5 · 2023: 1 · 2022: 5 · 2021: 7 · 2020: 6 · 2019: 3 · 2018: 6 · 2017: 1 · 2016: 9 · 2015: 9 · 2014: 15 · 2013: 18 · 2012: 17
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- IRIS (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion, other-oa)
- Funders
- National Institutes of Health (CA1 6038)
- National Cancer Institute (CA-16038, CA73796, P01CA016038, R01CA073796)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR 39190, R01AR039190)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- p21, Notch1, Wnt4, transcriptional repression, keratinocytes, E2F1, c-Myc, P300, histone hypoacetylation, Wnt signaling, tumor suppression, stem cell expansion, cell cycle regulation
- MeSH terms
- Transcription Factor HES-1, Animals, Cell Cycle, Cell Differentiation, Cell Division, Cells, Cultured, DNA-Binding Proteins, Nuclear Proteins, Promoter Regions, Genetic, Proto-Oncogene Proteins, Receptors, Cell Surface, RNA, Messenger, Transcription Factors, Transcription, Genetic, Signal Transduction, Trans-Activators, Down-Regulation, Keratinocytes, Proto-Oncogene Proteins c-myc, Mice, Knockout, Homeodomain Proteins, Cell Cycle Proteins, E2F Transcription Factors, E2F1 Transcription Factor, Cyclin-Dependent Kinase Inhibitor p21, E1A-Associated p300 Protein, Wnt Proteins, Mice, Basic Helix-Loop-Helix Proteins, Receptor, Notch1, Wnt4 Protein
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