MYC Releases Early Reprogrammed Human Cells from Proliferation Pause via Retinoblastoma Protein Inhibition
Open accessAbstract
Here, we report that MYC rescues early human cells undergoing reprogramming from a proliferation pause induced by OCT3/4, SOX2, and KLF4 (OSK). We identified ESRG as a marker of early reprogramming cells that is expressed as early as day 3 after OSK induction. On day 4, ESRG positive (+) cells converted to a TRA-1-60 (+) intermediate state. These early ESRG (+) or TRA-1-60 (+) cells showed a proliferation pause due to increased p16INK4A and p21 and decreased endogenous MYC caused by OSK. Exogenous MYC did not enhance the appearance of initial reprogramming cells but instead reactivated their proliferation and improved reprogramming efficiency. MYC increased expression of LIN41, which potently suppressed p21 post-transcriptionally. MYC suppressed p16 INK4A. These changes inactivated retinoblastoma protein (RB) and reactivated proliferation. The RB-regulated proliferation pause does not occur in immortalized fibroblasts, leading to high reprogramming efficiency even without exogenous MYC.
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c-Myc is not required for initiation of cellular reprogramming.
“Among the Yamanaka factors, c-Myc is an oncogene that reduces mouse lifespan20 and is not required for the initiation of cellular reprogramming21.”
From Reprogramming to recover youthful epigenetic information and restore vision (2020) · cites this paper as [21]
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References 58 · Cited by 37
- Authors
- Rand, T. A., Sutou, K., Tanabe, K., Jeong, D., Nomura, M., Kitaoka, F., Tomoda, E., Narita, M., Nakamura, M., Nakamura, M., Watanabe, A., Rulifson, E., Yamanaka, S., & Takahashi, K.
- Affiliations
- Gladstone Institutes (US)
- Center for iPS Cell Research and Application, Kyoto University (JP)
- Stanford Medicine (US)
- Corresponding author
- Yamanaka, Shinya
- Takahashi, Kazutoshi
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2018-04
- Volume
- 23
- Issue
- 2
- Pages
- 361-375
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC8241223
- OpenAlex
- W2797306832
- Cited by
- 37
- References
- 58
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 4 · 2023: 4 · 2022: 4 · 2021: 9 · 2020: 6 · 2019: 1 · 2018: 2
- FWCI
- 1.60
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Kyoto University Research Information Repository (Kyoto University) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institutes of Health (U01-HL098179, U01-HL100406)
- L. K. Whittier Foundation
- National Heart, Lung, and Blood Institute
- Japan Society for the Promotion of Science
- National Center for Research Resources (RR18928-01)
- Ministry of Education, Culture, Sports, Science and Technology
- Gladstone Institutes
- Roddenberry Foundation
- Japan Foundation for Applied Enzymology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- c-Myc, cellular reprogramming, retinoblastoma protein, Oct4, SOX2, KLF4, TRA-1-60, p16INK4a, p21, post-transcriptional regulation, cell cycle re-entry
- MeSH terms
- Tripartite Motif Proteins, Kruppel-Like Factor 4, Antigens, Surface, Cell Line, Humans, Phosphorylation, Proteoglycans, Transcription Factors, Retinoblastoma Protein, Proto-Oncogene Proteins c-myc, Cyclin-Dependent Kinase Inhibitor p16, RNA Interference, RNA, Small Interfering, Ubiquitin-Protein Ligases, Cell Proliferation, Induced Pluripotent Stem Cells, Cellular Reprogramming
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