Targeted Destruction of c-Myc by an Engineered Ubiquitin Ligase Suppresses Cell Transformation and Tumor Formation
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Given that expression of c-Myc is up-regulated in many human malignancies, targeted inactivation of this oncoprotein is a potentially effective strategy for cancer treatment. The ubiquitin-proteasome pathway of protein degradation is highly specific and can be engineered to achieve the elimination of undesirable proteins such as oncogene products. We have now generated a fusion protein (designated Max-U) that is composed both of Max, which forms a heterodimer with c-Myc, and of CHIP, which is a U box-type ubiquitin ligase (E3). Max-U physically interacted with c-Myc in transfected cells and promoted the ubiquitylation of c-Myc in vitro. It also reduced the stability of c-Myc in vivo, resulting in suppression of transcriptional activity dependent on c-Myc. Expression of Max-U reduced both the abundance of endogenous c-Myc in and the proliferation rate of a Burkitt lymphoma cell line. Furthermore, expression of Max-U but not that of a catalytically inactive mutant thereof markedly inhibited both the anchorage-independent growth in vitro of NIH 3T3 cells that overexpress c-Myc as well as tumor formation by these cells in nude mice. These findings indicate that the targeted destruction of c-Myc by an artificial E3 may represent an effective therapeutic strategy for certain human malignancies.
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Other groups have reported fusion bioPROTACs that degraded HER2, MYC and KRAS and demonstrated therapeutically relevant effects in human cancer cell lines and mouse xenograft tumour models overexpressing these POIs.
“Since then, other groups have reported fusion bioPROTACs that degraded the cancer targets human epidermal growth factor receptor 2 (HER2), MYC and KRAS and demonstrated therapeutically relevant effects in human cancer cell lines and mouse xenograft tumour models overexpressing these POIs16,17,211,212.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [17]
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PROTAC targeted protein degraders: the past is prologue
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- Authors
- Hatakeyama, S., Watanabe, M., Fujii, Y., & Nakayama, K. I.
- Affiliations
- Hokkaido University (JP)
- Kyushu University (JP)
- Venue
- Cancer Research
- Published
- 2005-09-01
- Volume
- 65
- Issue
- 17
- Pages
- 7874-7879
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2124061929
- Cited by
- 67
- References
- 35
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 4 · 2023: 6 · 2022: 3 · 2021: 3 · 2020: 4 · 2019: 5 · 2018: 2 · 2017: 4 · 2016: 7 · 2015: 5 · 2014: 4 · 2013: 2
- FWCI
- 1.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Kanae Foundation for the Promotion of Medical Science
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- c-Myc, Max, CHIP, E3 ubiquitin ligase, ubiquitination, protein degradation, ubiquitin-proteasome system, oncogene inactivation, Burkitt lymphoma, anchorage-independent growth, tumor formation, cell transformation, protein stability
- MeSH terms
- Animals, Burkitt Lymphoma, Cell Transformation, Neoplastic, Cloning, Molecular, HeLa Cells, Humans, Mice, Nude, Recombinant Fusion Proteins, Transfection, Protein Engineering, Proto-Oncogene Proteins c-myc, Ubiquitin, NIH 3T3 Cells, Ubiquitin-Protein Ligases, Mice
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