The ability of TRIM3 to induce growth arrest depends on RING-dependent E3 ligase activity.
The ability of TRIM3 to induce growth arrest depends on RING-dependent E3 ligase activity.
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DOI：
10.1042/bj20131288
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发表时间：
2014-03-15
期刊：
影响因子：
--
通讯作者：
Koff A
中科院分区：
文献类型：
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作者：
Raheja R;Liu Y;Hukkelhoven E;Yeh N;Koff A
TRIM（三方基序）-NHL家族成员brat和mei-P26的突变扰乱了转运扩增祖细胞的分化，导致肿瘤样表型。NHL（以NCL1， HT2A和LIN41重复命名）结构域对它们的生长抑制活性至关重要，并且它们可以以不依赖于ring的方式诱导细胞周期退出。TRIM3是哺乳动物TRIM-NHL亚家族中唯一真正的肿瘤抑制因子，与该家族的其他成员相似，其抑制细胞增殖的能力取决于NHL结构域。然而，trim3依赖性细胞周期退出是否需要RING结构域尚未被研究。在本研究中，我们证实了RING结构域是trim3诱导的生长抑制所必需的。此外，我们发现，在UbcH5a为首选E2的体外重组系统中，该结构域是促进p21泛素化所必需的。因此，TRIM3抑制生长的能力与其泛素化蛋白质的能力有关。
Mutation of the TRIM (tripartite motif)-NHL family members brat and mei-P26 perturb the differentiation of transit-amplifying progenitor cells resulting in tumour-like phenotypes. The NHL (named after the NCL1, HT2A and LIN41 repeat) domain is essential for their growth suppressive activity, and they can induce cell-cycle exit in a RING-independent manner. TRIM3 is the only bona fide tumour suppressor in the mammalian TRIM-NHL subfamily and similar to the other members of this family, its ability to inhibit cell proliferation depends on the NHL domain. However, whether the RING domain was required for TRIM3-dependent cell-cycle exit had not been investigated. In the present study, we establish that the RING domain is required for TRIM3-induced growth suppression. Furthermore, we show that this domain is necessary to promote ubiquitination of p21 in a reconstituted in vitro system where UbcH5a is the preferred E2. Thus the ability of TRIM3 to suppress growth is associated with its ability to ubiquitinate proteins.