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首页> 外文期刊>Journal of Pathology: Journal of the Pathological Society of Great Britain and Ireland >Genomic and phenotypic analysis reveals a key role for CCN1 (CYR61) in BAG3-modulated adhesion and invasion.
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Genomic and phenotypic analysis reveals a key role for CCN1 (CYR61) in BAG3-modulated adhesion and invasion.

机译：基因组和表型分析揭示了CCN1（CYR61）在BAG3调节的粘附和侵袭中的关键作用。

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摘要

Chaperone protein quantity may regulate the balance of proteins involved in invasion and malignancy. BAG3 is a co-chaperone and pro-survival protein that has been implicated in adhesion, migration, and metastasis. We reported that BAG3 overexpression in MDA435 human breast cancer cells results in a significant decrease in migration and adhesion to matrix molecules that is reversed upon deletion of the BAG3 proline-rich domain (dPXXP). We now hypothesize that transcriptional analysis would identify proteins involved in matrix-related processes that are regulated by BAG3 and/or its PXXP domain mutant. Expression array analysis of MDA435 cells overexpressing either wild-type BAG3 (FL) or dPXXP identified CCN1 as a BAG3 target protein. CCN1 is a known AP-1 target. Increased AP-1 transcriptional activity and AP-1 DNA-binding was found in MDA435 dPXXP cells. Consistent with these findings, CCN1 quantity and secretion were increased in dPXXP mutants but suppressed in FL cells; both BAG3 forms resulted in up-regulated CCN1 in HeLa cells. CCN1 silencing in the BAG3 FL overexpressors reduced the already low phospho-integrin beta1 in response to attachment on collagen IV. Matrigel invasion of HeLa cells engineered with the BAG3 constructs was enhanced in FL cells and minimal in dPXXP cells. CCN1 silencing blocked a greater percentage of the serum-induced invasion in FL cells than in dPXXP cells. This implies a context-dependent function of BAG3 on CCN1 and thus mesenchymal behaviour. CCN1 may be necessary for adhesion and matrix-related signalling in FL cells, abrogating a negative signal of the PXXP domain when BAG3 is intact. We propose that BAG3 regulates CCN1 expression to regulate tumour cell adhesion and migration.
机译：伴侣蛋白的量可以调节参与侵袭和恶性肿瘤的蛋白质的平衡。 BAG3是一种伴侣蛋白和促存活蛋白，与粘附，迁移和转移有关。我们报道了MDA435人乳腺癌细胞中BAG3的过度表达导致迁移和对基质分子的粘附力显着降低，这在缺失富含BAG3的脯氨酸的结构域（dPXXP）后被逆转。我们现在假设，转录分析将识别参与BAG3和/或其PXXP域突变体调控的基质相关过程的蛋白质。对过表达野生型BAG3（FL）或dPXXP的MDA435细胞的表达阵列分析确定CCN1为BAG3靶蛋白。 CCN1是已知的AP-1目标。在MDA435 dPXXP细胞中发现增加的AP-1转录活性和AP-1 DNA结合。与这些发现一致的是，dPXXP突变体中CCN1的数量和分泌增加，而FL细胞中CCN1的数量和分泌增加。两种BAG3形式均导致HeLa细胞中的CCN1上调。响应于胶原IV的附着，BAG3 FL过表达子中的CCN1沉默降低了已经很低的磷酸整合素beta1。用BAG3构建体改造的HeLa细胞的基质胶侵袭在FL细胞中增强，而在dPXXP细胞中则最小。与dPXXP细胞相比，CCN1沉默在FL细胞中阻断了更大比例的血清诱导的侵袭。这暗示了BAG3在CCN1上的上下文相关功能，因此是间充质行为。 CCN1对于FL细胞中的粘附和基质相关信号传导可能是必需的，当BAG3完整时，消除PXXP域的负信号。我们建议BAG3调节CCN1表达，以调节肿瘤细胞的粘附和迁移。

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