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

44 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

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Targeted destruction of c-Myc by an engineered ubiquitin ligase suppresses cell transformation and tumor formation'. Together they form a unique fingerprint.

  • Cite this