Different subcellular localizations and functions of human ARD1 variants.

Abstract

ARD1 is present in various species and has several variants derived from alternative splicing of mRNA. Previously, we reported differential biological functions and cellular distributions of mouse ARD1 (mARD1) variants. However, in comparison to mARD1 variants, human ARD1 (hARD1) variants have been rarely studied. In this study, we characterized a hARD1 variant, hARD1(131) and investigated its cellular activities. hARD1(131) mRNA was isolated from HeLa cells and sequenced. Sequence alignment revealed that, compared to hARD1(235), the most common form of hARD1, the mRNA sequence encoding hARD1131 possesses an altered reading frame due to a 46-bp deletion. Thus, hARD1(131) and hARD1(235) differ in their C-terminal regions with a partially deleted acetyltransferase domain at the C-terminus of hARD1(131). Moreover, hARD1(131) and hARD1(235) showed different subcellular localizations and biological functions. hARD1(131) was mostly localized in the cell nucleus, whereas hARD1(235) was primarily localized in the cytoplasm. In addition, hARD1(235) stimulated cell proliferation by upregulation of cyclin D1, however hARD1(131) had no influence on cyclin D1 expression and cell growth. Because hARD1(235) enhances cell proliferation by its autoacetylation activity, we examined the autoacetylation activity of hARD1(131) and observed that this function was absent in hARD1(131). These results suggest that human ARD1 variants have different effects on cell prolifer-ation, which may result from distinct subcellular localizations and autoacetylation activities.