Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
Oncogene. 2012 May 24;31(21):2668-79. doi: 10.1038/onc.2011.445. Epub 2011 Oct 10.
The transcription factor Sox4 is aberrantly expressed in many human tumors and can modulate tumorigenesis and metastases of murine tumors in vivo. However, mechanisms that control Sox4 function remain poorly defined. It has recently been observed that DNA damage increases Sox4 protein expression independently of Sox4 mRNA levels, suggesting an as yet undefined post-transcriptional mechanism regulating Sox4 expression and functionality. Here, we show that Sox4 protein is rapidly degraded by the proteasome as indicated by pharmacological inhibition with Mg132 and epoxymycin. Sox4 half-life was found to be less than 1 h as evident by inhibition of protein synthesis using cycloheximide. Ectopic expression of Sox4 deletion mutants revealed that the C-terminal 33 residues of Sox4 were critical in modulating its degradation in a polyubiquitin-independent manner. Syntenin, a Sox4 binding partner, associates with this domain and was found to stabilize Sox4 expression. Syntenin-induced stabilization of Sox4 correlated with Sox4-syntenin relocalization to the nucleus, where both proteins accumulate. Syntenin overexpression or knockdown in human tumor cell lines was found to reciprocally modulate Sox4 protein expression and transcriptional activity implicating its role as a regulator of Sox4. Taken together, our data demonstrate that the Sox4 C-terminal domain regulates polyubiquitin-independent proteasomal degradation of Sox4 that can be modulated by interaction with syntenin. As aberrant Sox4 expression has been found associated with many human cancers, modulation of Sox4 proteasomal degradation may impact oncogenesis and metastatic properties of tumors.
转录因子 Sox4 在许多人类肿瘤中异常表达，可在体内调节小鼠肿瘤的发生和转移。然而，控制 Sox4 功能的机制仍知之甚少。最近观察到，DNA 损伤可独立于 Sox4 mRNA 水平增加 Sox4 蛋白表达，表明存在一种尚未定义的转录后机制来调节 Sox4 的表达和功能。在这里，我们表明 Sox4 蛋白可被蛋白酶体迅速降解，这可通过用 Mg132 和环氧霉素进行药理学抑制来证实。通过使用环己酰亚胺抑制蛋白质合成，发现 Sox4 的半衰期小于 1 小时。过表达 Sox4 缺失突变体表明 Sox4 的 C 末端 33 个残基对于以多泛素非依赖性方式调节其降解至关重要。Sox4 结合伴侣 syntenin 与该结构域结合，并被发现稳定 Sox4 的表达。Syntenin 诱导 Sox4 稳定与 Sox4-syntenin 重新定位到细胞核相关，这两种蛋白都在细胞核中积累。在人肿瘤细胞系中过表达或敲低 syntenin 发现可相互调节 Sox4 蛋白表达和转录活性，表明它作为 Sox4 的调节剂的作用。总之，我们的数据表明 Sox4 C 末端结构域调节 Sox4 的多泛素非依赖性蛋白酶体降解，该过程可通过与 syntenin 的相互作用来调节。由于异常的 Sox4 表达已与许多人类癌症相关，因此 Sox4 蛋白酶体降解的调节可能会影响肿瘤的发生和转移特性。
