The ubiquitin ligase HectH9 regulates transcriptional activation by Myc and is essential for tumor cell proliferation.
The Myc oncoprotein forms a binary activating complex with its partner protein, Max, and a ternary repressive complex that, in addition to Max, contains the zinc finger protein Miz1. Here we show that the E3 ubiquitin ligase HectH9 ubiquitinates Myc in vivo and in vitro, forming a lysine 63-linked polyubiquitin chain. Miz1 inhibits this ubiquitination. HectH9-mediated ubiquitination of Myc is required for transactivation of multiple target genes, recruitment of the coactivator p300, and induction of cell proliferation by Myc. HectH9 is overexpressed in multiple human tumors and is essential for proliferation of a subset of tumor cells. Our results suggest that site-specific ubiquitination regulates the switch between an activating and a repressive state of the Myc protein, and they suggest a strategy to interfere with Myc function in vivo.
Adhikary
Sovana
S
Institute for Molecular Biology and Tumor Research, University of Marburg, Emil-Mannkopff-Str.2, 35033 Marburg, Germany.
Marinoni
Federica
F
Hock
Andreas
A
Hulleman
Esther
E
Popov
Nikita
N
Beier
Rudi
R
Bernard
Sandra
S
Quarto
Micaela
M
Capra
Maria
M
Goettig
Stephan
S
Kogel
Ulrike
U
Scheffner
Martin
M
Helin
Kristian
K
Eilers
Martin
M
D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000378:metabolism; D016259:Genes, myc; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D051379:Mice; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D025821:Polyubiquitin / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology*; D050880:p300-CBP Transcription Factors / Q000378:metabolism
D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C107961:ZBTB17 protein, human; D025821:Polyubiquitin; D050880:p300-CBP Transcription Factors; C502830:HUWE1 protein, human; D044767:Ubiquitin-Protein Ligases