Cancer-causing mutations in a novel transcription-dependent nuclear export motif of VHL abrogate oxygen-dependent degradation of hypoxia-inducible factor

Mireille Khacho, Karim Mekhail, Karine Pilon-Larose, Josianne Payette, Stephen Lee

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

It is thought that degradation of nuclear proteins by the ubiquity lation system requires nuclear-cytoplasmic trafficking of E3 ubiquitin ligases. The von Hippel-Lindau (VHL) tumor suppressor protein is the substrate recognition component of a Cullin-2-containing E3 ubiquitin ligase that recruits hypoxia-inducible factor (HIF) for oxygen-dependent degradation. We demonstrated that VHL engages in nuclear-cytoplasmic trafficking that requires ongoing transcription to promote efficient HIF degradation. Here, we report the identification of a discreet motif, DXGX2DX2L, that directs transcription-dependent nuclear export of VHL and which is targeted by naturally occurring mutations associated with renal carcinoma and polycythemia in humans. The DXGX2DX2L motif is also found in other proteins, including poly(A)-binding protein 1, to direct its transcription-dependent nuclear export. We define DXGX2DX 2L as TD-NEM (transcription-dependent nuclear export motif), since inhibition of transcription by actinomycin D or 5,6-dichlorobenzimidazole abrogates its nuclear export activity. Disease-causing mutations of key residues of TD-NEM restrain the ability of VHL to efficiently mediate oxygen-dependent degradation of HIF by altering its nuclear export dynamics without affecting interaction with its substrate. These results identify a novel nuclear export motif, further highlight the role of nuclear-cytoplasmic shuttling of E3 ligases in degradation of nuclear substrates, and provide evidence that disease-causing mutations can target subcellular trafficking.

Original languageEnglish (US)
Pages (from-to)302-314
Number of pages13
JournalMolecular and Cellular Biology
Volume28
Issue number1
DOIs
StatePublished - Jan 2008
Externally publishedYes

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Cell Nucleus Active Transport
Oxygen
Mutation
Ubiquitin-Protein Ligases
Neoplasms
Von Hippel-Lindau Tumor Suppressor Protein
Poly(A)-Binding Proteins
Cullin Proteins
Polycythemia
Dactinomycin
Nuclear Proteins
Hypoxia
Carcinoma
Kidney

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Cancer-causing mutations in a novel transcription-dependent nuclear export motif of VHL abrogate oxygen-dependent degradation of hypoxia-inducible factor. / Khacho, Mireille; Mekhail, Karim; Pilon-Larose, Karine; Payette, Josianne; Lee, Stephen.

In: Molecular and Cellular Biology, Vol. 28, No. 1, 01.2008, p. 302-314.

Research output: Contribution to journalArticle

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