The brain acid-soluble protein 1 (BASP1) interferes with the oncogenic capacity of MYC and its binding to calmodulin
The brain acid-soluble protein 1 (BASP1) interferes with the oncogenic capacity of MYC and its binding to calmodulin
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DOI：
10.1002/1878-0261.12636
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发表时间：
2020-01-30
影响因子：
6.6
通讯作者：
Bister, Klaus
中科院分区：
文献类型：
--
作者：
Hartl, Markus;Puglisi, Kane;Bister, Klaus
MYC蛋白是具有致癌潜力的转录因子，其控制基本细胞过程，如细胞增殖、代谢、分化和凋亡。MYC基因是一个主要的癌症驱动因素，MYC蛋白水平升高是大多数人类癌症的标志。我们以前已经表明，脑酸溶性蛋白1基因（BASP 1）特异性下调的v-myc癌基因和异位BASP 1表达抑制v-myc诱导的细胞转化。BASP 1蛋白的11个氨基酸的效应结构域与钙传感器钙调蛋白（CaM）相互作用，并主要负责这种抑制功能。我们最近还报道了CaM与所有MYC变体蛋白相互作用，并且异位CaM增加了v-Myc蛋白的反式激活和转化潜力。在这里，我们表明，过量的BASP 1或合成BASP 1效应结构域肽的存在下，导致从钙调素的v-Myc的位移。在共表达v-Myc和BASP 1的细胞中，v-Myc的蛋白稳定性降低，这可能是v-Myc被抑制的原因。此外，v-Myc触发的转录激活和细胞转化的抑制是由异位钙调素补偿，这表明BASP 1介导的退出钙调素从v-Myc的抑制是一个至关重要的事件。鉴于BASP 1的肿瘤抑制作用（最近也报道了其对人类癌症的作用），基于BASP 1效应结构域的小化合物或肽可用于针对具有高MYC表达的肿瘤的药物开发策略。
The MYC protein is a transcription factor with oncogenic potential controlling fundamental cellular processes such as cell proliferation, metabolism, differentiation, and apoptosis. The MYC gene is a major cancer driver, and elevated MYC protein levels are a hallmark of most human cancers. We have previously shown that the brain acid-soluble protein 1 gene (BASP1) is specifically downregulated by the v-myc oncogene and that ectopic BASP1 expression inhibits v-myc-induced cell transformation. The 11-amino acid effector domain of the BASP1 protein interacts with the calcium sensor calmodulin (CaM) and is mainly responsible for this inhibitory function. We also reported recently that CaM interacts with all MYC variant proteins and that ectopic CaM increases the transactivation and transformation potential of the v-Myc protein. Here, we show that the presence of excess BASP1 or of a synthetic BASP1 effector domain peptide leads to displacement of v-Myc from CaM. The protein stability of v-Myc is decreased in cells co-expressing v-Myc and BASP1, which may account for the inhibition of v-Myc. Furthermore, suppression of v-Myc-triggered transcriptional activation and cell transformation is compensated by ectopic CaM, suggesting that BASP1-mediated withdrawal of CaM from v-Myc is a crucial event in the inhibition. In view of the tumor-suppressive role of BASP1 which was recently also reported for human cancer, small compounds or peptides based on the BASP1 effector domain could be used in drug development strategies aimed at tumors with high MYC expression.