title: HAX-1 is a nucleocytoplasmic shuttling protein with a possible role in mRNA processing.
abstract: HAX-1 is a multi-functional protein that is involved in the regulation of apoptosis, cell motility and calcium homeostasis. It is also reported to bind RNA: it associates with structural motifs present in the 3' untranslated regions of at least two transcripts, but the functional significance of this binding remains unknown. Although HAX-1 has been detected in various cellular compartments, it is predominantly cytoplasmic. Our detailed localization studies of HAX-1 isoforms revealed partial nuclear localization, the extent of which depends on the protein isoform. Further studies demonstrated that HAX-1 is in fact a nucleocytoplasmic shuttling protein, dependent on the exportin 1 nuclear export receptor. Systematic mutagenesis allowed identification of the two nuclear export signals in the HAX-1 sequence. HAX-1 nuclear accumulation was observed after inhibition of nuclear export by leptomycin B, but also after specific cellular stress. The biological role of HAX-1 nuclear localization and shuttling remains to be established, but the HAX-1 transcript-binding properties suggest that it may be connected to mRNA processing and surveillance. In this study, HAX-1 status was shown to influence mRNA levels of DNA polymerase β, one of the HAX-1 mRNA targets, although this effect becomes pronounced only after specific stress is applied. Moreover, HAX-1 tethering to the reporter transcript caused a significant decrease in its expression. Additionally, the HAX-1 co-localization with P-body markers, reported here, implies a role in mRNA processing. These results suggest that HAX-1 may be involved in the regulation of expression of bound transcripts, possibly as part of the stress response.
authors.affiliation: Department of Molecular Biology, Cancer Center Institute, Warsaw, Poland. ewag@coi.waw.pl
authors.forename: Ewa A
authors.initials: EA
authors.lastname: Grzybowska
authors.forename: Valery
authors.initials: V
authors.lastname: Zayat
authors.forename: Ryszard
authors.initials: R
authors.lastname: Konopiński
authors.forename: Alicja
authors.initials: A
authors.lastname: Trębińska
authors.forename: Maria
authors.initials: M
authors.lastname: Szwarc
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Sarnowska
authors.forename: Ewelina
authors.initials: E
authors.lastname: Macech
authors.forename: Jarosław
authors.initials: J
authors.lastname: Korczyński
authors.forename: Anna
authors.initials: A
authors.lastname: Knapp
authors.forename: Janusz A
authors.initials: JA
authors.lastname: Siedlecki
mesh_terms: D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D018053:Arsenites / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D019951:DNA Polymerase beta / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D028884:Karyopherins / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D049790:Nuclear Export Signals; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D021381:Protein Transport; D012323:RNA Processing, Post-Transcriptional; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013312:Stress, Physiological; D013723:Teratogens / Q000494:pharmacology; D000097606:Exportin 1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018053:Arsenites; D002352:Carrier Proteins; D019951:DNA Polymerase beta; D047908:Intracellular Signaling Peptides and Proteins; D028884:Karyopherins; D049790:Nuclear Export Signals; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; D013723:Teratogens; D000097606:Exportin 1 Protein; C104759:HAX1 protein, human; C510653:Hax1 protein, rat; C015001:arsenite