Deregulation of FOXO3A during prostate cancer progression.
Deregulation of FOXO3A during prostate cancer progression.
复制标题
前列腺癌进展过程中 FOXO3A 的失调。
DOI：
10.3892/ijo_00000291
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发表时间：
2009-06
影响因子：
5.2
通讯作者：
Gupta S
中科院分区：
文献类型：
--
作者：
Shukla S;Shukla M;Maclennan GT;Fu P;Gupta S
叉头盒转录因子FOXO 3A是一种重要的细胞功能调节因子，被认为是一种肿瘤抑制因子。我们研究了FOXO 3A活性的改变是否发生在前列腺肿瘤发生中。我们的研究表明，FOXO 3A活性是负调控Akt/PKB通过翻译后修饰。在前列腺癌细胞中，Akt激活导致FOXO 3A及其结合伴侣蛋白14-3-3在胞质溶胶中的积累增加。细胞质中较高水平的FOXO 3A与丝氨酸253磷酸化相关，这是其核排斥的原因。PC-3细胞中显性负Akt途径增加了FOXO 3A在细胞核中的积累，导致下游靶点MnSOD的上调。相反，稳定的DU 145-Akt过表达细胞表现出细胞核中FOXO 3A水平降低。在前列腺肿瘤标本中观察到类似的发现，其中随着Gleason分级的增加，观察到前列腺肿瘤中FOXO 3A和14-3-3的显著细胞质积累，与良性前列腺细胞中的完全核积累相反。这些发现与FOXO 3 A DNA结合活性降低以及FOXO 3 A转录活性随肿瘤分级增加而下调沿着。我们的研究结果表明，肿瘤相关的FOXO 3A的改变和再分布是前列腺癌病因学中的常见事件。
Forkhead box transcription factor FOXO3A is an important regulator of cellular function, is thought to act as a tumor suppressor. We studied whether alterations in FOXO3A activity occur in prostate tumorigenesis. Our studies demonstrate that FOXO3A activity is negatively regulated by Akt/PKB through posttranslational modifications. In prostate cancer cells, Akt activation causes increased accumulation of FOXO3A and its binding chaperone protein 14-3-3 in the cytosol. Higher levels of FOXO3A in the cytosol correlated with phosphorylation at Ser253, which accounted for its nuclear exclusion. Dominant negative Akt approach in PC-3 cells increased FOXO3A accumulation in the nucleus, causing upregulation of the downstream target, MnSOD. Conversely, stable DU145-Akt over-expressing cells exhibited decreased FOXO3A levels in the nucleus. Similar findings were noted in prostate tumor specimens, in which marked cytoplasmic accumulation of FOXO3A and 14-3-3 in prostate tumors was observed with increasing Gleason grade, in contrast to exclusively nuclear accumulation in benign prostate cells. These findings correlate with decreased FOXO3A DNA binding activity along with down modulation of FOXO3A transcriptional activity with increasing tumor grade. Our findings demonstrate that tumor associated alterations and redistribution of FOXO3A are frequent events in the etiology of prostate cancer.
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DOI：
10.1083/jcb.200307056
发表时间：
2004-01-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bakker WJ;Blázquez-Domingo M;Kolbus A;Besooyen J;Steinlein P;Beug H;Coffer PJ;Löwenberg B;von Lindern M;van Dijk TB
通讯作者：
van Dijk TB
影响因子：
3.9
作者：
Karger, Stefan;Weidinger, Carl;Fuhrer, Dagmar
通讯作者：
Fuhrer, Dagmar
影响因子：
3.9
作者：
Murphy, Coleen T.
通讯作者：
Murphy, Coleen T.
影响因子：
--
作者：
Wayne, Chad M.;Fan, Heng-Yu;Richards, JoAnne S.
通讯作者：
Richards, JoAnne S.
影响因子：
4.8
作者：
Birkenkamp, Kim U.;Essafi, Abdelkader;Coffer, Paul J.
通讯作者：
Coffer, Paul J.