Negative regulation of C/EBPbeta1 by sumoylation in breast cancer cells.
Negative regulation of C/EBPbeta1 by sumoylation in breast cancer cells.
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DOI：
10.1371/journal.pone.0025205
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Sealy L
中科院分区：
文献类型：
--
作者：
Atwood AA;Jerrell R;Sealy L
类小泛素化是一种翻译后修饰，通常在疾病如癌症中失调。转录因子是SUMO修饰的常见靶点，SUMO修饰可以影响靶蛋白的亚细胞定位、转录活性和稳定性。C/EBPbeta 1是一个这样的转录因子，由SUMO-2/3修饰。非小泛素化C/EBP β 1，p52-C/EBP β 1，在正常乳腺上皮细胞中表达，但在乳腺癌细胞系中不表达，并在癌基因诱导的衰老（一种肿瘤抑制机制）中发挥作用。虽然在乳腺癌细胞系中通过免疫印迹未观察到p52-C/EBP β 1，但当用C/EBP β 1特异性抗体对乳腺癌细胞系进行免疫印迹分析时，观察到较高分子量条带。我们发现，外源性表达的C/EBP β 1在乳腺癌细胞中被sumoylated，并且我们在乳腺癌细胞系的抗C/EBP β 1免疫印迹中观察到的较高分子量条带是sumoylated C/EBP β 1。磷酸化常常增强类小泛素化，并且磷酸化级联在乳腺癌细胞中被激活。我们证明，C/EB β 1 Thr 235的Erk-2磷酸化增强了C/EB β 1在体外的sumoylation。此外，类小泛素化的C/EBP β 1在Thr 235上磷酸化，并且Thr 235突变为丙氨酸导致C/EBP β 1类小泛素化的减少。最后，使用C/EBPbeta 1-SUMO融合蛋白，我们表明C/EBPbeta 1的组成性类小化完全阻止了其诱导表达hTERT的WI 38成纤维细胞衰老的能力。因此，乳腺癌细胞中C/EBP β 1的summolylation可能是规避癌基因诱导的衰老的机制。
Sumoylation is a post-translational modification that is oftentimes deregulated in diseases such as cancer. Transcription factors are frequent targets of sumoylation and modification by SUMO can affect subcellular localization, transcriptional activity, and stability of the target protein. C/EBPbeta1 is one such transcription factor that is modified by SUMO-2/3. Non-sumoylated C/EBPbeta1, p52-C/EBPbeta1, is expressed in normal mammary epithelial cells but not breast cancer cell lines and plays a role in oncogene-induced senescence, a tumor suppressive mechanism. Although p52-C/EBPbeta1 is not observed via immunoblot in breast cancer cell lines, higher molecular weight bands are observed when breast cancer cell lines are subjected to immunoblot analysis with a C/EBPbeta1-specific antibody. We show that exogenously expressed C/EBPbeta1 is sumoylated in breast cancer cells, and that the higher molecular weight bands we observe in anti-C/EBPbeta1 immunoblots of breast cancer cell lines is sumoylated C/EBPbeta1. Phosphorylation oftentimes enhances sumoylation, and phosphorylation cascades are activated in breast cancer cells. We demonstrate that phosphorylation of C/EBPbeta1Thr235 by Erk-2 enhances sumoylation of C/EBPbeta1 in vitro. In addition, sumoylated C/EBPbeta1 is phosphorylated on Thr235 and mutation of Thr235 to alanine leads to a decrease in sumoylation of C/EBPbeta1. Finally, using a C/EBPbeta1-SUMO fusion protein we show that constitutive sumoylation of C/EBPbeta1 completely blocks its capability to induce senescence in WI38 fibroblasts expressing hTERT. Thus, sumolylation of C/EBPbeta1 in breast cancer cells may be a mechanism to circumvent oncogene-induced senescence.
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