The deubiquitinating enzyme BAP1 regulates cell growth via interaction with HCF-1

Yuichi Machida, Yuka Machida, Ajay A. Vashisht, James A. Wohlschlegel, Anindya Dutta

Research output: Contribution to journalArticle

143 Citations (Scopus)

Abstract

The deubiquitinating enzyme BRCA1-associated protein 1 (BAP1) possesses growth inhibitory activity and functions as a tumor suppressor. In this study we report that BAP1 also plays positive roles in cell proliferation. BAP1 depletion by RNAi inhibits cell proliferation as does overexpression of a dominant negative mutant of BAP1. Mass spectrometry analyses of copurified proteins revealed that BAP1 is associated with factors involved in chromatin modulation and transcriptional regulation. We show that the interaction with host cell factor-1 (HCF-1), a cell-cycle regulator composed of HCF-1N and HCF-1C, is critical for the BAP1-mediated growth regulation. We found that HCF-1N is modified with Lys-48-linked polyubiquitin chains on its Kelch domain. The HCF-1 binding motif of BAP1 is required for interaction with HCF-1N and mediates deubiquitination of HCF-1N by BAP1. The importance of the BAP1-HCF-1 interaction is underscored by the fact that growth suppression by the dominant negative BAP1 mutant is entirely dependent on the HCF-1 binding motif. These results suggest that BAP1 regulates cell proliferation by deubiquitinating HCF-1.

Original languageEnglish (US)
Pages (from-to)34179-34188
Number of pages10
JournalJournal of Biological Chemistry
Volume284
Issue number49
DOIs
StatePublished - Dec 4 2009

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Host Factor 1 Protein
BRCA1 Protein
Cell growth
Enzymes
Growth
Proteins
Cell proliferation
Cell Proliferation
Deubiquitinating Enzymes
Polyubiquitin
RNA Interference

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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The deubiquitinating enzyme BAP1 regulates cell growth via interaction with HCF-1. / Machida, Yuichi; Machida, Yuka; Vashisht, Ajay A.; Wohlschlegel, James A.; Dutta, Anindya.

In: Journal of Biological Chemistry, Vol. 284, No. 49, 04.12.2009, p. 34179-34188.

Research output: Contribution to journalArticle

Machida, Yuichi ; Machida, Yuka ; Vashisht, Ajay A. ; Wohlschlegel, James A. ; Dutta, Anindya. / The deubiquitinating enzyme BAP1 regulates cell growth via interaction with HCF-1. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 49. pp. 34179-34188.
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