Transcriptional role of cyclin D1 in development revealed by a genetic-proteomic screen
Open accessAbstract
Cyclin D1 belongs to the core cell cycle machinery, and it is frequently overexpressed in human cancers. The full repertoire of cyclin D1 functions in normal development and oncogenesis is unclear at present. Here we developed Flag- and haemagglutinin-tagged cyclin D1 knock-in mouse strains that allowed a high-throughput mass spectrometry approach to search for cyclin D1-binding proteins in different mouse organs. In addition to cell cycle partners, we observed several proteins involved in transcription. Genome-wide location analyses (chromatin immunoprecipitation coupled to DNA microarray; ChIP-chip) showed that during mouse development cyclin D1 occupies promoters of abundantly expressed genes. In particular, we found that in developing mouse retinas-an organ that critically requires cyclin D1 function-cyclin D1 binds the upstream regulatory region of the Notch1 gene, where it serves to recruit CREB binding protein (CBP) histone acetyltransferase. Genetic ablation of cyclin D1 resulted in decreased CBP recruitment, decreased histone acetylation of the Notch1 promoter region, and led to decreased levels of the Notch1 transcript and protein in cyclin D1-null (Ccnd1(-/-)) retinas. Transduction of an activated allele of Notch1 into Ccnd1(-/-) retinas increased proliferation of retinal progenitor cells, indicating that upregulation of Notch1 signalling alleviates the phenotype of cyclin D1-deficiency. These studies show that in addition to its well-established cell cycle roles, cyclin D1 has an in vivo transcriptional function in mouse development. Our approach, which we term 'genetic-proteomic', can be used to study the in vivo function of essentially any protein.
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Various noncanonical CDK-dependent and/or CDK-independent roles for nuclear cyclin D1 have been reported, for example, in transcription and DNA double-strand break repair.
“various noncanonical CDK-dependent and/or CDK-independent roles for nuclear cyclin D1 have been reported, for example, in transcription and DNA double-strand break repair (47, 48).”
From A genome-wide screen reveals that Dyrk1A kinase promotes nucleotide excision repair by preventing aberrant overexpression of cyclin D1 and p21 (2023) · cites this paper as [47]
The paper reports an in vivo transcriptional role for cyclin D1 in mouse development and discusses proposed CDK-independent transcriptional functions (Abstract; page not provided). It does not address DNA double-strand break repair, so that example in the citing sentence is not supported by this source. (LLM, conf=0.87)
Experimental — accuracy not yet measuredCyclin D1 and the CDK4-related kinase CDK6 can associate with target genes and function as transcriptional regulators.
“Previous studies revealed that Cyclin D140,41 as well as the CDK4-related kinase CDK642 can associate with target genes and function as transcriptional regulators.”
From CDK4 inhibition diminishes p53 activation by MDM2 antagonists (2018) · cites this paper as [41]
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References 31 · Cited by 276
- Authors
- Bienvenu, F., Jirawatnotai, S., Elias, J. E., Meyer, C. A., Mizeracka, K., Marson, A., Frampton, G. M., Cole, M. F., Odom, D. T., Odajima, J., Geng, Y., Zagozdzon, A., Jecrois, M., Young, R. A., Liu, X. S., Cepko, C. L., Gygi, S. P., & Sicinski, P.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Harvard University (US)
- Whitehead Institute for Biomedical Research (US)
- Cancer Research UK (GB)
- ORCID
- Venue
- Nature
- Published
- 2010-01
- Volume
- 463
- Issue
- 7279
- Pages
- 374-378
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2943587
- OpenAlex
- W2128360853
- Cited by
- 276
- References
- 31
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 7 · 2023: 13 · 2022: 9 · 2021: 13 · 2020: 19 · 2019: 20 · 2018: 13 · 2017: 17 · 2016: 18 · 2015: 17 · 2014: 22 · 2013: 28 · 2012: 34
- FWCI
- 15.47
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
- PMC
- Funders
- Cancer Research UK (15603, A15603)
- U.S. Public Health Service (R01 EYO9676)
- National Human Genome Research Institute (HG004069, R01HG004069, HG3456, R01HG002668, R01HG003456)
- National Eye Institute (R01EY008064, R01EY009676)
- National Cancer Institute (R01CA108420, P01CA080111, P01CA109901)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- cyclin D1, transcriptional regulation, Notch1, retinal development, CREB-binding protein, histone acetylation, promoter binding, retinal progenitor cells, Notch signaling, developmental gene regulation, carcinogenesis, cell cycle, ChIP-chip, CCND1
- MeSH terms
- Alleles, Animals, Promoter Regions, Genetic, Protein Binding, Retina, Mass Spectrometry, Stem Cells, Transcription, Genetic, Genome, Gene Expression Regulation, Developmental, Cyclin D1, Oligonucleotide Array Sequence Analysis, Proteomics, Chromatin Immunoprecipitation, CREB-Binding Protein, Mice, Rats, Histone Acetyltransferases, Receptor, Notch1, High-Throughput Screening Assays
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