Characterization of ARD1 variants in mammalian cells
Characterization of ARD1 variants in mammalian cells
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DOI：
10.1016/j.bbrc.2005.12.018
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发表时间：
2006-02-10
影响因子：
3.1
通讯作者：
Kim, KW
中科院分区：
文献类型：
--
作者：
Kim, SH;Park, JA;Kim, KW
据报道，小鼠ARD 1（mARD 1）通过乙酰化赖氨酸残基和增强HIF-1 α泛素化和降解来负调节低氧诱导因子1 α（IIIF-1 α）蛋白。然而.最近报道人ARD 1（hARD 1）不影响HIF-1 α的稳定性。为了进一步探索两种直系同源物的活性，鉴定并表征了三种小鼠（mARDl（198）、mARDl（225）、mARDl（235））和两种人（hARDl（131）、hARDl（235））变体。其中，mARDl（225）先前被报道为HIF-1 α的新型负调节因子。氨基酸序列分析显示，mARD 1（225）的C-末端区域（aa 158 - 225）与小鼠和人ARD 1（235）的C-末端区域完全不同，尽管所有三种蛋白质共享高度保守的N-乙酰转移酶结构域（aa 45 - 130）。就HIF-1 α稳定性和乙酰化活性评价ARD 1变体的作用。有趣的是，mARDl（225）强烈降低HIF-1 α的水平并增加乙酰化程度，而mARDl（235）和hARDl（235）变体对HIF-1 α稳定性和乙酰化的影响弱得多。这些结果表明，ARD 1变体可能对HIF-1 α的稳定性和乙酰化有不同的影响，这可能反映了仍有待确定的多种生物学功能。(c)2005年爱思唯尔公司All rights reserved.
Mouse ARD1 (mARD1) has been reported to negatively regulate the hypoxia-inducible factor 1 alpha (IIIF-1 alpha) protein by acetylating a lysine residue and enhancing HIF-1 alpha ubiquitination and degradation. However. it was recently reported that human ARD1 (hARD1) does not affect HIF-1 alpha stability. To further explore the activities of the two orthologs, three mouse (mARDl(198), mARDl(225), mARDl(235)) and two human (hARDl(131), hARDl(235)) variants were identified and characterized. Among these, mARDl(225) was previously reported as a novel negative regulator of HIF-1 alpha. Amino acid sequence analysis showed that the C-terminal region (aa 158 225) of mARDl(225), completely differs from those of mouse and human ARDl(235), although all three proteins share a well-conserved N-acetyltransferase domain (aa 45 130). The effects of ARDl variants were evaluated with respect to HIF-1 alpha stability and acetylation activity. Interestingly, mARDl(225) strongly decreased the level of HIF-1 alpha and increased the extent of acetylation, whereas mARDl(235) and hARDl(235) variants had a much weaker effect on HIF-1 alpha stability and acetylation. These results suggest that ARD1 variants might have different effects on HIF-1 alpha stability and acetylation, which may reflect diverse biological functions that remain to be determined. (c) 2005 Elsevier Inc. All rights reserved.