A 19S proteasomal subunit cooperates with an ERK MAPK-regulated degron to regulate accumulation of Fra-1 in tumour cells
A 19S proteasomal subunit cooperates with an ERK MAPK-regulated degron to regulate accumulation of Fra-1 in tumour cells
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DOI：
10.1038/onc.2011.375
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发表时间：
2012-04-01
期刊：
影响因子：
8
通讯作者：
Dhillon, A. S.
中科院分区：
文献类型：
--
作者：
Pakay, J. L.;Diesch, J.;Dhillon, A. S.
Fos相关抗原-1（Fra-1）是激活蛋白-1（AP-1）转录因子超家族的成员，其在多种癌症中过表达，包括结肠癌、乳腺癌、肺癌、膀胱癌和脑癌。高Fra-1水平与增强的细胞增殖、存活、迁移和侵袭相关。尽管其频繁过表达，但调节Fra-1蛋白在肿瘤细胞中积累的分子机制尚不清楚。在这里，我们表明，营业额的Fra-1，这不需要泛素化，是由两个不同的机制，协会与19 S蛋白酶体亚基，TBP-1，并通过C-末端降解决定子，其作用独立于TBP-1，但调节RAS-ERK（细胞外信号调节激酶）信号。TBP-1耗竭稳定了Fra-1，并进一步增加了其在表达RAS-ERK途径癌基因的肿瘤细胞中的水平。这些作用与AP-1转录活性增加相关。我们认为，在Fra-1降解，协会与TBP-1提供了一种机制，泛素独立的蛋白酶体识别，而蛋白质的C末端调节其随后的蛋白水解加工。Oncogene（2012）31，1817-1824; doi：10.1038/onc.2011.375; 2011年8月29日在线发表
Fos-related antigen-1 (Fra-1) is a member of the Activator Protein-1 (AP-1) transcription factor superfamily that is overexpressed in a variety of cancers, including colon, breast, lung, bladder and brain. High Fra-1 levels are associated with enhanced cell proliferation, survival, migration and invasion. Despite its frequent overexpression, the molecular mechanisms that regulate the accumulation of Fra-1 proteins in tumour cells are not well understood. Here, we show that turnover of Fra-1, which does not require ubiquitylation, is cooperatively regulated by two distinct mechanisms-association with the 19S proteasomal subunit, TBP-1, and by a C-terminal degron, which acts independently of TBP-1, but is regulated by RAS-ERK (extracellular signal-regulated kinase) signalling. TBP-1 depletion stabilized Fra-1 and further increased its levels in tumour cells expressing RAS-ERK pathway oncogenes. These effects correlated with increased AP-1 transcriptional activity. We suggest that during Fra-1 degradation, association with TBP-1 provides a mechanism for ubiquitin-independent proteasomal recognition, while the C terminus of the protein regulates its subsequent proteolytic processing. Oncogene (2012) 31, 1817-1824; doi: 10.1038/onc.2011.375; published online 29 August 2011