Dominant-negative c-Jun (TAM67) target genes: HMGA1 is required for tumor promoter-induced transformation
Dominant-negative c-Jun (TAM67) target genes: HMGA1 is required for tumor promoter-induced transformation
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DOI：
10.1038/sj.onc.1207581
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发表时间：
2004-05-27
期刊：
影响因子：
8
通讯作者：
Colburn, NH
中科院分区：
文献类型：
--
作者：
Dhar, A;Hu, J;Colburn, NH
转录因子AP - 1（激活蛋白-1）的激活对于肿瘤促进和恶性表型的维持是必需的。许多在肿瘤进展中起作用的受AP - 1调控的基因已被确定。然而，驱动肿瘤诱导的受AP - 1调控的基因仍有待明确。先前的研究已经证实，显性负性c - Jun（TAM67）的表达抑制佛波醇12 - 十四酰基 - 13 - 乙酸酯（TPA）诱导的AP - 1反式激活以及小鼠表皮JB6/P +细胞的转化和小鼠皮肤癌变中的肿瘤促进。在这项研究中，我们利用对肿瘤促进敏感的JB6/P +细胞来鉴定受AP - 1调控的TAM67靶基因，并确定一个靶基因在转化中的因果重要性。用来自有或无TAM67表达的经TPA处理的P +细胞的RNA对2700个cDNA微阵列进行查询。在TAM表达抑制TPA诱导的转化的条件下，微阵列分析确定了由TPA诱导且被TAM67抑制的六个基因的一个子集。所确定的基因之一，高迁移率族蛋白A1（Hmga1）在P +细胞中由TPA诱导，但在抗转化的P细胞中不被诱导。我们表明，TAM67抑制TPA对结构转录因子HMGA1的诱导，这种诱导依赖于细胞外信号调节激酶（ERK）的激活，并由AP - 1介导。转染到P +细胞中的HMGA1反义构建体阻断了HMGA1蛋白表达并抑制了TPA诱导的转化，这表明HMGA1是转化所必需的。然而，HMGA1并不足以导致转化，因为HMGA1a或HMGA1b的过表达并没有使P -细胞具有转化敏感性。尽管HMGA1的表达依赖于ERK，但它不是转化所必需的唯一依赖于ERK的事件，因为它不足以挽救ERK缺陷的P -细胞。我们的研究表明：（a）当TAM67抑制AP - 1和转化时，它靶向相对较少数量的基因；（b）HMGA1，一个TAM67靶基因，与转化有因果关系，因此是癌症预防的一个潜在重要靶点。
Activation of the transcription factor AP-1 (activator protein-1) is required for tumor promotion and maintenance of malignant phenotype. A number of AP-1-regulated genes that play a role in tumor progression have been identified. However, AP-1-regulated genes driving tumor induction are yet to be defined. Previous studies have established that expression of a dominant-negative c-Jun (TAM67) inhibits phorbol 12-tetradecanoyl-13-acetate (TPA)-induced AP-1 transactivation as well as transformation in mouse epidermal JB6/P+ cells and tumor promotion in mouse skin carcinogenesis. In this study, we utilized the tumor promotion-sensitive JB6/P+ cells to identify AP-1-regulated TAM67 target genes and to establish causal significance in transformation for one target gene. A 2700 cDNA microarray was queried with RNA from TPA-treated P+ cells with or without TAM67 expression. Under conditions in which TAM expression inhibited TPA-induced transformation, microarray analysis identified a subset of six genes induced by TPA and suppressed by TAM67. One of the identified genes, the high-mobility group protein A1 (Hmga1) is induced by TPA in P+, but not in transformation-resistant P cells. We show that TPA induction of the architectural transcription factor HMGA1 is inhibited by TAM67, is extracellular-signal-regulated kinase (ERK)-activation dependent, and is mediated by AP-1. HMGA1 antisense construct transfected into P+ cells blocked HMGA1 protein expression and inhibited TPA-induced transformation indicating that HMGA1 is required for transformation. HMGA1 is not however sufficient as HMGA1a or HMGA1b overexpression did not confer transformation sensitivity on P- cells. Although HMGA1 expression is ERK dependent, it is not the only ERK-dependent event required for transformation because it does not suffice to rescue ERK-deficient P- cells. Our study shows (a) TAM 67 when it inhibits AP-1 and transformation, targets a relatively small number of genes; (b) HMGA1, a TAM67 target gene, is causally related to transformation and therefore a potentially important target for cancer prevention.