Targeted destruction of c-Myc by an engineered ubiquitin ligase suppresses cell transformation and tumor formation

Shigetsugu Hatakeyama, Masashi Watanabe, Yo Fujii, Keiichi I. Nakayama

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)7874-7879
Number of pages6
JournalCancer Research
Volume65
Issue number17
DOIs
Publication statusPublished - Sep 1 2005

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Ligases
Ubiquitin
Oncogene Proteins
Neoplasms
NIH 3T3 Cells
Ubiquitin-Protein Ligases
Burkitt Lymphoma
Ubiquitination
Proteasome Endopeptidase Complex
Nude Mice
Proteolysis
Cell Line
Growth
Proteins
In Vitro Techniques
Therapeutics

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Targeted destruction of c-Myc by an engineered ubiquitin ligase suppresses cell transformation and tumor formation. / Hatakeyama, Shigetsugu; Watanabe, Masashi; Fujii, Yo; Nakayama, Keiichi I.

In: Cancer Research, Vol. 65, No. 17, 01.09.2005, p. 7874-7879.

Research output: Contribution to journalArticle

Hatakeyama, Shigetsugu ; Watanabe, Masashi ; Fujii, Yo ; Nakayama, Keiichi I. / Targeted destruction of c-Myc by an engineered ubiquitin ligase suppresses cell transformation and tumor formation. In: Cancer Research. 2005 ; Vol. 65, No. 17. pp. 7874-7879.
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