Matsushima-Nishiu M, Unoki M, Ono K, Tsunoda T, Minaguchi T, Kuramoto H, Nishida M, Satoh T, Tanaka T, Nakamura Y
Laboratories of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
Cancer Res. 2001 May 1;61(9):3741-9.
The PTEN tumor suppressor gene encodes a multifunctional phosphatase that plays an important role in inhibiting the phosphatidylinositol-3-kinase pathway and downstream functions that include activation of Akt/protein kinase B, cell survival, and cell proliferation. Enforced expression of PTEN in various cancer cell lines decreases cell proliferation through arrest of the cell cycle, accompanied in some cases by induction of apoptosis. We used cDNA microarrays containing 4009 cDNAs to examine changes in gene-expression profiles when exogenous PTEN was induced in PTEN-defective cells. The microarrays and subsequent semi-quantitative reverse transcription-PCR analysis revealed transcriptional stimulation of 99 genes and repression of 72 genes. Some of the differentially expressed genes already had been implicated in cell proliferation, differentiation, apoptosis, or cell cycle control, e.g., overexpression of PTEN-induced transactivation of cyclin-dependent inhibitor 1B (p27Kip1) and 2B (p15INK4B), members of the TNF receptor family, tumor necrosis factor-associated genes, and members of the Notch-signaling and Mad families. To our knowledge this is the first report of transactivation of those genes by PTEN. The genes differentially expressed in our experiments also included many whose correlation with cancer development had not been recognized before. Our data should contribute to a greater understanding of the broad spectrum of ways in which PTEN affects intracellular signaling pathways. Analysis of expression profiles with microarrays appears to be a powerful approach for identifying anticancer genes and/or disease-specific targets for cancer therapy.
PTEN肿瘤抑制基因编码一种多功能磷酸酶，该酶在抑制磷脂酰肌醇-3-激酶途径及包括Akt/蛋白激酶B激活、细胞存活和细胞增殖在内的下游功能中发挥重要作用。在各种癌细胞系中强制表达PTEN可通过使细胞周期停滞来降低细胞增殖，在某些情况下还伴有凋亡诱导。我们使用包含4009个cDNA的cDNA微阵列来检测在PTEN缺陷细胞中诱导外源性PTEN时基因表达谱的变化。微阵列及随后的半定量逆转录-PCR分析显示99个基因转录激活，72个基因表达受抑制。一些差异表达基因已被认为与细胞增殖、分化、凋亡或细胞周期调控有关，例如PTEN诱导细胞周期蛋白依赖性激酶抑制因子1B（p27Kip1）和2B（p15INK4B）、TNF受体家族成员、肿瘤坏死因子相关基因以及Notch信号和Mad家族成员的反式激活。据我们所知，这是PTEN对这些基因进行反式激活的首次报道。我们实验中差异表达的基因还包括许多之前未被认识到与癌症发展相关的基因。我们的数据应有助于更深入地理解PTEN影响细胞内信号通路的广泛方式。用微阵列分析表达谱似乎是一种识别抗癌基因和/或癌症治疗疾病特异性靶点的有力方法。
