FBXO31 is the chromosome 16q24.3 senescence gene, a candidate breast tumor suppressor, and a component of an SCF complex
FBXO31 is the chromosome 16q24.3 senescence gene, a candidate breast tumor suppressor, and a component of an SCF complex
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DOI：
10.1158/0008-5472.can-05-0936
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发表时间：
2005-12-15
期刊：
影响因子：
11.2
通讯作者：
Callen, DF
中科院分区：
文献类型：
--
作者：
Kumar, R;Neilsen, PM;Callen, DF
位于乳腺癌16q24.3杂合区的BAC基因转移到乳腺癌细胞系后可以恢复细胞衰老，我们的研究表明，FBX031虽然位于该BAC基因的远端，但可以诱导乳腺癌细胞株MCF-7细胞衰老，是可能的候选衰老基因。FBX031具有与肿瘤抑制物一致的特性，因为FBX031在两个乳腺癌细胞系中的异位表达抑制了塑料上的集落生长，并抑制了MCF-7细胞系的细胞增殖。此外，与正常乳腺组织相比，乳腺肿瘤细胞系和原发肿瘤组织中FBX031的表达水平均下调。FBX031在乳腺癌细胞株MCF-10A和SKBR3中受细胞周期调控，在G(2)晚期和G(1)早期表达最强。在乳腺癌细胞系MDA-MB-468中异位表达FBX031导致细胞在细胞周期G(1)期聚集。FBX031含有一个F-box结构域，并与Skp1、Roc-1和cullin-1蛋白相关联，表明FBX031是SCF泛素化复合体的一个组成部分。我们认为，FBX031通过产生针对特定底物的SCFFBXO31复合体发挥肿瘤抑制作用，这些底物对细胞周期的正常执行至关重要，用于泛素化和随后的降解。
A BAC located in the 16q24.3 breast cancer loss of heterozygosity region was previously shown to restore cellular senescence when transferred into breast tumor cell lines, We have shown that FBX031, although located just distal to this BAC, can induce cellular senescence in the breast cancer cell line MCF-7 and is the likely candidate senescence gene. FBX031 has properties consistent with a tumor suppressor, because ectopic expression of FBX031 in two breast cancer cell lines inhibited colony growth on plastic and inhibited cell proliferation in the MCF-7 cell line. In addition, compared with the relative expression in normal breast, levels of FBX031 were down-regulated in breast tumor cell lines and primary tumors. FBX031 was cell cycle regulated in the breast cell lines MCF-10A and SKBR3 with maximal expression from late G(2) to early G(1) phase. Ectopic expression of FBX031 in the breast cancer cell line MDA-MB-468 resulted in the accumulation of cells at the G(1) phase of the cell cycle. FBX031 contains an F-box domain and is associated with the proteins Skp1, Roc-1, and Cullin-1, suggesting that FBX031 is a component of a SCF ubiquitination complex. We propose that FBX031 functions as a tumor suppressor by generating SCFFBXO31 complexes that target particular substrates, critical for the normal execution of the cell cycle, for ubiquitination and subsequent degradation.