Inhibition of Myc-induced cell transformation by brain acid-soluble protein 1 (BASP1)
Inhibition of Myc-induced cell transformation by brain acid-soluble protein 1 (BASP1)
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DOI：
10.1073/pnas.0812101106
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发表时间：
2009-04-07
影响因子：
11.1
通讯作者：
Bister, Klaus
中科院分区：
文献类型：
--
作者：
Hartl, Markus;Nist, Andrea;Bister, Klaus
Myc癌蛋白的细胞转化涉及具有内在致癌或肿瘤抑制潜能的特定靶基因的转录激活或抑制。我们已经确定BASP1(CAP-23，NAP-22)基因是Myc抑制的一个新的靶点。酸性的25 kDa BASP1蛋白最初是从大鼠和鸡脑中分离出来的一种皮质细胞骨架相关蛋白，但也在其他组织和亚细胞位置发现了这种蛋白。在v-myc癌基因转化的成纤维细胞中，BASP1mRNA和蛋白的表达被特异性地抑制，而在其他致癌因子转化的细胞中则不受抑制。在未翻译的外显子1的5‘端，BASP1基因包含两个外显子，分别由一个58kbp的内含子和一个Myc应答的调节区组成。逆转录病毒载体中BASP1和v-myc的双顺反子表达阻断了v-myc诱导的细胞转化。此外，BASP1的异位表达使成纤维细胞对v-myc随后的细胞转化产生抵抗，外源BASP1基因导入v-myc转化的细胞后，转化的表型显著减弱。BASP1对v-myc诱导的细胞转化的抑制也阻止了已知Myc靶基因的转录激活或抑制。突变分析表明，含有肉豆蔻酰化位点、钙调蛋白结合域和可能的核定位信号的碱性N-末端结构域是BASP1抑制功能所必需的。我们的结果表明，BASP1基因的下调在myc诱导的肿瘤发生中是一个必要的事件，并将BASP1蛋白定义为一个潜在的肿瘤抑制因子。
Cell transformation by the Myc oncoprotein involves transcriptional activation or suppression of specific target genes with intrinsic oncogenic or tumor-suppressive potential, respectively. We have identified the BASP1 (CAP-23, NAP-22) gene as a novel target suppressed by Myc. The acidic 25-kDa BASP1 protein was originally isolated as a cortical cytoskeleton-associated protein from rat and chicken brain, but has also been found in other tissues and subcellular locations. BASP1 mRNA and protein expression is specifically suppressed in fibroblasts transformed by the v-myc oncogene, but not in cells transformed by other oncogenic agents. The BASP1 gene encompasses 2 exons separated by a 58-kbp intron and a Myc-responsive regulatory region at the 5' boundary of untranslated exon 1. Bicistronic expression of BASP1 and v-myc from a retroviral vector blocks v-myc-induced cell transformation. Furthermore, ectopic expression of BASP1 renders fibroblasts resistant to subsequent cell transformation by v-myc, and exogenous delivery of the BASP1 gene into v-myc-transformed cells leads to significant attenuation of the transformed phenotype. The inhibition of v-myc-induced cell transformation by BASP1 also prevents the transcriptional activation or repression of known Myc target genes. Mutational analysis showed that the basic N-terminal domain containing a myristoylation site, a calmodulin binding domain, and a putative nuclear localization signal is essential for the inhibitory function of BASP1. Our results suggest that down-regulation of the BASP1 gene is a necessary event in myc-induced oncogenesis and define the BASP1 protein as a potential tumor suppressor.