Nucleocytoplasmic shuttling of IPAS by its unique nuclear import and export signals unshared with other HIF-3a splice variants

Satoru Torii, Kohei Sakaki, Miki Otomo, Kyohei Saka, Ken Ichi Yasumoto, Kazuhiro Sogawa

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

Inhibitory Per/Arnt/Sim (PAS) domain protein (IPAS) is a splice variant of hypoxia-inducible factor (HIF)-3a, and possesses two entirely different functions. One is as a transcriptional repressor against HIF-dependent hypoxic gene activation. The other is as a pro-apoptotic factor by direct binding to the pro-survival protein Bcl-xL and its related proteins on mitochondria. Presently, the regulatory mechanism that determines the intracellular distribution of IPAS to fulfill each of the two functions is unknown. As a first step towards elucidation of the mechanism, nucleocytoplasmic transport signals of IPAS were explored. A bipartite-like nuclear localization signal (NLS) was found in the N-terminal region by the deletion and mutation analysis of EGFP-IPAS. In addition, the helix-loop-helix domain showed weak nuclear import/retention activity. A leptomycin B-sensitive nuclear export signal (NES) was localized in the C-terminal region of the protein. A proline-rich region supported the NES activity. These NLS and NES are not carried by the other variants of HIF-3a due to differential exon usage. These results strongly suggest that IPAS is a nucleocytoplasmic shuttling protein.

Original languageEnglish
Pages (from-to)561-567
Number of pages7
JournalJournal of biochemistry
Volume154
Issue number6
DOIs
Publication statusPublished - 2013 Dec

Keywords

  • CRM1
  • Hypoxia-inducible factor
  • IPAS
  • NES
  • NLS

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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