Transcriptomic and phylogenetic analysis of Kpna genes: a family of nuclear import factors modulated in xenobiotic-mediated liver growth.
OBJECTIVE
We have identified a member of the karyopherin (importin) alpha family of nuclear import factors as being modulated in rat liver following exposure to the hypolipidaemic and liver growth agent Wy-14,643. To examine the hypothetical role of this protein family as a checkpoint in receptor-mediated signalling, we characterized the rat karyopherin alpha (Kpna) gene family and present cDNA sequences and gene structures for all six rat Kpna genes. Further, we have assembled a comprehensive panel of Kpna coding regions from a range of metazoa, which we have subjected to phylogenetic analysis: This represents by far the most complete phylogenetic study of metazoan karyopherins, including several evolutionary intermediates not previously examined. The phylogeny reveals three Kpna subfamilies with distinct, conserved gene structures, shedding light on the evolutionary origins of this multigene family in metazoa.


RESULTS
Using quantitative PCR, we have analysed Kpna transcript levels in 44 rat tissues; Kpna transcripts show a wide variation in their distribution both in absolute and relative terms, suggestive of specialized roles for each member. We also demonstrate that Kpna genes are regulated in rat liver and isolated hepatocytes in a xenobiotic-specific manner for a number of chemically distinct liver growth agents.


CONCLUSIONS
In light of the crucial role of nuclear import in mediating the genomic changes elicited through nuclear receptor activation, we postulate that changes in the levels of specific karyopherins alpha during xenobiotic-mediated liver growth represent an important component of the cellular response to the external stimuli that trigger these events.
Plant
Kathryn E
KE
School of Biomedical and Molecular Sciences, University of Surrey, Guildford, GU2 7XH, UK.
Everett
David M
DM
Gordon Gibson
G
G
Lyon
Jon
J
Plant
Nick J
NJ
D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D017373:Cyproterone Acetate / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D006529:Hepatomegaly / Q000139:chemically induced; D008658:Inactivation, Metabolic / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000254:growth & development; D008297:Male; D008954:Models, Biological; D008969:Molecular Sequence Data; D005810:Multigene Family; D010802:Phylogeny; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D015262:Xenobiotics / Q000494:pharmacology; D028901:alpha Karyopherins / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism* / Q000502:physiology
D011743:Pyrimidines; D015262:Xenobiotics; D028901:alpha Karyopherins; D017373:Cyproterone Acetate; D003907:Dexamethasone; C006253:pirinixic acid