LincRNA-p21 Activates p21 In cis to Promote Polycomb Target Gene Expression and to Enforce the G1/S Checkpoint
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The p53-regulated long noncoding RNA lincRNA-p21 has been proposed to act in trans via several mechanisms ranging from repressing genes in the p53 transcriptional network to regulating mRNA translation and protein stability. To further examine lincRNA-p21 function, we generated a conditional knockout mouse model. We find that lincRNA-p21 predominantly functions in cis to activate expression of its neighboring gene, p21. Mechanistically, we show that lincRNA-p21 acts in concert with hnRNP-K as a coactivator for p53-dependent p21 transcription. Additional phenotypes of lincRNA-p21 deficiency could be attributed to diminished p21 levels, including deregulated expression and altered chromatin state of some Polycomb target genes, a defective G1/S checkpoint, increased proliferation rates, and enhanced reprogramming efficiency. These findings indicate that lincRNA-p21 affects global gene expression and influences the p53 tumor suppressor pathway by acting in cis as a locus-restricted coactivator for p53-mediated p21 expression.
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In the case of lincRNA-p21, the low stability and low copy numbers found make it unlikely that lincRNA-p21 directly regulates many target genes.
“In the case of lincRNA-p21, the low stability and low copy numbers found make it unlikely that lincRNA-p21 directly regulates many target genes.129”
From Census and evaluation of p53 target genes (2017) · cites this paper as [129]
lincRNA-p21 supports p21 upregulation in response to p53 activation.
“One such mechanism was suggested for lincRNA-p21, which supports p21 upregulation in response to p53 activation.129”
From Census and evaluation of p53 target genes (2017) · cites this paper as [129]
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- Authors
- Dimitrova, N., Zamudio, J. R., Jong, R. M., Soukup, D., Resnick, R., Sarma, K., Ward, A. J., Raj, A., Lee, J. T., Sharp, P. A., & Jacks, T.
- Affiliations
- Koch Institute for Integrative Cancer Research At MIT (US)
- Massachusetts General Hospital (US)
- Ionis Pharmaceuticals (United States) (US)
- University of Pennsylvania (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Jacks, Tyler
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2014-06
- Volume
- 54
- Issue
- 5
- Pages
- 777-790
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC4103188
- OpenAlex
- W2017844161
- Cited by
- 445
- References
- 39
- Citations by year
- 2026: 12 · 2025: 13 · 2024: 19 · 2023: 30 · 2022: 33 · 2021: 47 · 2020: 46 · 2019: 37 · 2018: 49 · 2017: 61 · 2016: 48 · 2015: 39 · 2014: 10
- FWCI
- 16.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- PMC
- Funders
- Howard Hughes Medical Institute
- Damon Runyon Cancer Research Foundation
- National Institutes of Health (1dp2od008514-01)
- Ludwig Center for Molecular Oncology
- Ludwig Center at Harvard
- National Cancer Institute (R01CA133404, P01CA042063, P30CA014051)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- lincRNA-p21, long non-coding RNA, p21, p53, cis-acting regulation, hnRNP K, transcriptional coactivator, p53-dependent transcription, Polycomb target genes, G1/S checkpoint, cell proliferation, cellular reprogramming, conditional knockout mice, chromatin state
- MeSH terms
- Animals, Cells, Cultured, Transcriptional Activation, Mice, Knockout, Epigenesis, Genetic, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p21, Mice, Transcriptome, G1 Phase Cell Cycle Checkpoints, RNA, Long Noncoding, Polycomb-Group Proteins
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