人肝癌细胞抑癌基因PTEN的表达及其启动子的调控研究
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摘要
PTEN是1997年克隆得到的第一个具有磷酸酶活性的抑癌基因,定位于人染色体10q23.3。它与许多肿瘤的发生或发展有着密切关系,目前已在很多肿瘤中发现有PTEN的缺失与突变;而且,PTEN在细胞信号转导和正常胚胎发育过程中均有重要作用。PTEN蛋白由403个氨基酸残基组成,含有双专一性磷酸酶结构域;这种蛋白不仅具有蛋白磷酸酶活性,而且具有脂质磷酸酶活性;它既能使磷酸化的丝氨酸/苏氨酸残基脱磷酸,也能使磷酸酪氨酸脱磷酸,还能使磷脂酰肌醇-3,4,5-三磷酸(phosphatidylinositol(3,4,5)-trisphosphate,PIP3) 的3位脱磷酸。通过对PI3-K/Akt、 MAPK、FAK等重要的细胞内信号转导通路的调节,PTEN可以调控细胞生长、增殖、粘附与迁移,并能促进细胞凋亡。
PTEN的功能主要是通过其磷酸酶的活性来实现的,为了研究PTEN磷酸酶活性与BEL-7404肝癌细胞生物学行为之间的关系,我们将含野生型或特定酶活性缺失突变型的PTEN的表达质粒转染到BEL-7404肝癌细胞中。实验发现,PTEN可以抑制7404肝癌细胞的生长与增殖,还可以抑制细胞的克隆形成与细胞迁移,并且影响了7404肝癌细胞的周期。进一步分析显示,PTEN的这些功能主要是通过PTEN蛋白质的磷酸酶活性来实现的。此外,我们采用Northern blot和Western blot等方法,研究了7株人肝癌细胞(HHCC)与L02细胞(肝永生化细胞株)中PTEN的mRNA表达水平和蛋白质表达水平,实验发现,与L02细胞相比,7株人肝癌细胞中PTEN的mRNA表达水平与蛋白质表达水平均下降,其中HepG2细胞株中的PTEN蛋白质几乎检测不到,而且PTEN蛋白质的变化趋势与PTEN mRNA的变化趋势基本一致,两者之间存在相关关系(p<0.01)。我们利用RT-PCR的方法克隆了8株细胞PTEN的编码框,序列分析的结果显示,在8株细胞的PTEN编码框中均未发现片段缺失或点突变,说明7株肝癌细胞中PTEN表达的差异不是由突变所致,提示PTEN表达的转录水平调控占有重要地位。
为了探讨肝癌细胞中PTEN的转录调控机制,我们克隆了PTEN的全长启动子区域,通过构建启动子系列缺失的报告质粒,通过瞬时转染并结合报告基因活性测定方法,我们确定PTEN的核心启动子区定位在-1118到-778区域的341bp的片段内,而-1389到-778这个612bp片段区域是PTEN启动子的最高活性区。我们将PTEN启动子的最高活性区片段转染到8株细胞中,结果发现,PTEN启动子在8株细胞中的活性高低不一,且各株细胞间活性变化趋势与PTEN mRNA水平的变化趋势相
一致,而且存在相关关系,进一步提示,肝癌细胞中PTEN表达的转录水平调控可能处于很重要的地位。
启动子转录活性的调控是基因表达调控的主要方式。通常通过反式作用因子与启动子上的顺式作用元件结合,启动或调节基因的转录。生物学软件分析发现,PTEN启动子的核心区有10个潜在的转录因子结合位点,我们分别用8核苷酸序列替代每一转录因子结合位点,得到10 个单一转录因子结合位点突变的报告质粒(△pGl3-612),将上述报告质粒分别转染到SMMC-7721和L02细胞中,结果发现,MAZ 1、MAZ 2、p53和Sp1结合位点对于PTEN启动子表现最佳活性是必需的。将Sp1或MAZ的表达质粒分别与上述突变型或野生型启动子报告质粒,共转染上述2株细胞,结果发现Sp1和MAZ可以明显上调PTEN启动子的活性,此上调作用主要依赖于MAZ 1、MAZ 2结合位点。EMSA结果显示,以Sp1为标记探针形成的条带可以被公认的高亲和力的Sp1非标记探针竞争性抑制,也能够被非标记的MAZ探针竞争性抑制;以MAZ为标记探针形成的条带,可以被非标记的MAZ探针竞争性抑制,也能够被公认的高亲和力的Sp1非标记探针竞争性抑制, 提示Sp1和MAZ可以结合在相同的序列上。以上结果表明MAZ 1、MAZ 2位点参与Sp1与MAZ对PTEN启动子活性的调节。综上所述,我们得出结论,Sp1和MAZ可以通过与-1035到-1016区域的序列结合,上调PTEN基因的表达。
PTEN was identified as a tumor suppressor gene in 1997 located on human chromosome 10q23.3, which was mutated or deleted in a variety of sporadic cancers. PTEN encodes a dual-specificity phosphatase, which is able to dephosphorylate either phospho-tyrosine or phospho-serine/threonine residues. PTEN, also acts as a lipid phosphatase, specifically cleaves the D3 phosphate of phosphatidylinositol (3,4,5)-triphosphate (PIP3), an important intracellular second messenger, produced by the activity of PI3-kinase. By blocking the activation of Akt, FAK or MAPK pathway, PTEN regulates cellular processes such as proliferation, adhesion, migration, cell cycling, and apoptosis. PTEN implicated not only in tumorigenesis and progression but also in normal embryogenesis development. So it is very important to study the PTEN transcriptional regulation in human hepatocellular carcinoma cells (HHCC).
To investgate the phosphotase fouction of PTEN protein, we transfected the wild-type PTEN or mutant PTEN, which lost lipid phosphotase activity or lost both lipid phosphotase activity and protein phosphotase activity, expression plasmids into the BEL-7404 cells, It was found that PTEN can suppress the proliferation, migration, clony formation and cell cycle of BEL-7404 cells, and these effects were mainly attributed to its phosphatase activity. Northern blot and Western blot analysis showed that the PTEN protein level and PTEN mRNA level were decreased in human hepatocellular carcinoma (HHCC) cell lines compared with that in L02 cells. The profile of PTEN protein level in each of 8 cell lines closely parallelized with its PTEN mRNA, which means the variation of PTEN protein mostly dependent on change of PTEN mRNA. The DNA sequencing of PTEN ORF which obtained by RT-PCR showed that there was no any mutation in it. These results demonstrated that the decrease of PTEN expression in HHCC cell lines was not caused by PTEN mutation, and may be to due to the transcriptional or post- transcriptional regulation of PTEN gene.
It is well known that the regulation of gene promoter activity plays an important role in gene transcription regualtion. In an attempt to analyze the activity of PTEN
promoter in HHCC, we isolated a DNA fragment containing 5'-flanking region and the 5'-untranslated region(5'-UTR)from PTEN gene, and performed series promoter deletion. The deletion analysis of PTEN promoter showed that the fragment of 612bp (-1389/-778) can produce maximum promoter activity in 8 cell lines and the core region of PTEN promoter was resided within the 341bp (-1118/-778) fragment. After the transfection of pGL3-612bp (-1389/-778) into 8 cell lines, we found the profile of PTEN promoter activity was almost parallelized with the profiles of PTEN mRNA and PTEN protein in 8 cell lines. Taken together, we concluded that the downregulation of PTEN expression in 7 HCC cell lines probably does not owing to the mutation of PTEN but maybe mainly attributed to the activity lost of PTEN promoter.
To identify the functional cis-elements in the core region of PTEN promoter, 10 potential elements (binding sites) were examined by using 8 bp substitutive mutation respectively in SMMC-7721 cells and L02 cells. It was suggested that two MAZ binding sites, located at the region from -1035 to -1016, are very important for the optimal PTEN promoter activity. Electrophoretic mobility shift assays (EMSA) showed that the MAZ and Sp1 could cross bind to MAZ and Sp1 binding sites. The results of co-transfection of either Sp1 or MAZ expression plasmids with luciferase reporter plasmids contain wild-type or mutated PTEN promoters revealed that both Sp1 and MAZ can induce the activation of PTEN promoter through -1035 to -1016 bases containing MAZ binding sites, but not through the sequence from -937 to -923 containing Sp1 binding site. The results in this study suggested that the zinc-finger proteins Sp1 and MAZ could up-regulate the PTEN expression via binding to the sequence from -1035 to -1016 in SMMC-7721 cells and L02 cells.
PTEN的功能主要是通过其磷酸酶的活性来实现的,为了研究PTEN磷酸酶活性与BEL-7404肝癌细胞生物学行为之间的关系,我们将含野生型或特定酶活性缺失突变型的PTEN的表达质粒转染到BEL-7404肝癌细胞中。实验发现,PTEN可以抑制7404肝癌细胞的生长与增殖,还可以抑制细胞的克隆形成与细胞迁移,并且影响了7404肝癌细胞的周期。进一步分析显示,PTEN的这些功能主要是通过PTEN蛋白质的磷酸酶活性来实现的。此外,我们采用Northern blot和Western blot等方法,研究了7株人肝癌细胞(HHCC)与L02细胞(肝永生化细胞株)中PTEN的mRNA表达水平和蛋白质表达水平,实验发现,与L02细胞相比,7株人肝癌细胞中PTEN的mRNA表达水平与蛋白质表达水平均下降,其中HepG2细胞株中的PTEN蛋白质几乎检测不到,而且PTEN蛋白质的变化趋势与PTEN mRNA的变化趋势基本一致,两者之间存在相关关系(p<0.01)。我们利用RT-PCR的方法克隆了8株细胞PTEN的编码框,序列分析的结果显示,在8株细胞的PTEN编码框中均未发现片段缺失或点突变,说明7株肝癌细胞中PTEN表达的差异不是由突变所致,提示PTEN表达的转录水平调控占有重要地位。
为了探讨肝癌细胞中PTEN的转录调控机制,我们克隆了PTEN的全长启动子区域,通过构建启动子系列缺失的报告质粒,通过瞬时转染并结合报告基因活性测定方法,我们确定PTEN的核心启动子区定位在-1118到-778区域的341bp的片段内,而-1389到-778这个612bp片段区域是PTEN启动子的最高活性区。我们将PTEN启动子的最高活性区片段转染到8株细胞中,结果发现,PTEN启动子在8株细胞中的活性高低不一,且各株细胞间活性变化趋势与PTEN mRNA水平的变化趋势相
一致,而且存在相关关系,进一步提示,肝癌细胞中PTEN表达的转录水平调控可能处于很重要的地位。
启动子转录活性的调控是基因表达调控的主要方式。通常通过反式作用因子与启动子上的顺式作用元件结合,启动或调节基因的转录。生物学软件分析发现,PTEN启动子的核心区有10个潜在的转录因子结合位点,我们分别用8核苷酸序列替代每一转录因子结合位点,得到10 个单一转录因子结合位点突变的报告质粒(△pGl3-612),将上述报告质粒分别转染到SMMC-7721和L02细胞中,结果发现,MAZ 1、MAZ 2、p53和Sp1结合位点对于PTEN启动子表现最佳活性是必需的。将Sp1或MAZ的表达质粒分别与上述突变型或野生型启动子报告质粒,共转染上述2株细胞,结果发现Sp1和MAZ可以明显上调PTEN启动子的活性,此上调作用主要依赖于MAZ 1、MAZ 2结合位点。EMSA结果显示,以Sp1为标记探针形成的条带可以被公认的高亲和力的Sp1非标记探针竞争性抑制,也能够被非标记的MAZ探针竞争性抑制;以MAZ为标记探针形成的条带,可以被非标记的MAZ探针竞争性抑制,也能够被公认的高亲和力的Sp1非标记探针竞争性抑制, 提示Sp1和MAZ可以结合在相同的序列上。以上结果表明MAZ 1、MAZ 2位点参与Sp1与MAZ对PTEN启动子活性的调节。综上所述,我们得出结论,Sp1和MAZ可以通过与-1035到-1016区域的序列结合,上调PTEN基因的表达。
PTEN was identified as a tumor suppressor gene in 1997 located on human chromosome 10q23.3, which was mutated or deleted in a variety of sporadic cancers. PTEN encodes a dual-specificity phosphatase, which is able to dephosphorylate either phospho-tyrosine or phospho-serine/threonine residues. PTEN, also acts as a lipid phosphatase, specifically cleaves the D3 phosphate of phosphatidylinositol (3,4,5)-triphosphate (PIP3), an important intracellular second messenger, produced by the activity of PI3-kinase. By blocking the activation of Akt, FAK or MAPK pathway, PTEN regulates cellular processes such as proliferation, adhesion, migration, cell cycling, and apoptosis. PTEN implicated not only in tumorigenesis and progression but also in normal embryogenesis development. So it is very important to study the PTEN transcriptional regulation in human hepatocellular carcinoma cells (HHCC).
To investgate the phosphotase fouction of PTEN protein, we transfected the wild-type PTEN or mutant PTEN, which lost lipid phosphotase activity or lost both lipid phosphotase activity and protein phosphotase activity, expression plasmids into the BEL-7404 cells, It was found that PTEN can suppress the proliferation, migration, clony formation and cell cycle of BEL-7404 cells, and these effects were mainly attributed to its phosphatase activity. Northern blot and Western blot analysis showed that the PTEN protein level and PTEN mRNA level were decreased in human hepatocellular carcinoma (HHCC) cell lines compared with that in L02 cells. The profile of PTEN protein level in each of 8 cell lines closely parallelized with its PTEN mRNA, which means the variation of PTEN protein mostly dependent on change of PTEN mRNA. The DNA sequencing of PTEN ORF which obtained by RT-PCR showed that there was no any mutation in it. These results demonstrated that the decrease of PTEN expression in HHCC cell lines was not caused by PTEN mutation, and may be to due to the transcriptional or post- transcriptional regulation of PTEN gene.
It is well known that the regulation of gene promoter activity plays an important role in gene transcription regualtion. In an attempt to analyze the activity of PTEN
promoter in HHCC, we isolated a DNA fragment containing 5'-flanking region and the 5'-untranslated region(5'-UTR)from PTEN gene, and performed series promoter deletion. The deletion analysis of PTEN promoter showed that the fragment of 612bp (-1389/-778) can produce maximum promoter activity in 8 cell lines and the core region of PTEN promoter was resided within the 341bp (-1118/-778) fragment. After the transfection of pGL3-612bp (-1389/-778) into 8 cell lines, we found the profile of PTEN promoter activity was almost parallelized with the profiles of PTEN mRNA and PTEN protein in 8 cell lines. Taken together, we concluded that the downregulation of PTEN expression in 7 HCC cell lines probably does not owing to the mutation of PTEN but maybe mainly attributed to the activity lost of PTEN promoter.
To identify the functional cis-elements in the core region of PTEN promoter, 10 potential elements (binding sites) were examined by using 8 bp substitutive mutation respectively in SMMC-7721 cells and L02 cells. It was suggested that two MAZ binding sites, located at the region from -1035 to -1016, are very important for the optimal PTEN promoter activity. Electrophoretic mobility shift assays (EMSA) showed that the MAZ and Sp1 could cross bind to MAZ and Sp1 binding sites. The results of co-transfection of either Sp1 or MAZ expression plasmids with luciferase reporter plasmids contain wild-type or mutated PTEN promoters revealed that both Sp1 and MAZ can induce the activation of PTEN promoter through -1035 to -1016 bases containing MAZ binding sites, but not through the sequence from -937 to -923 containing Sp1 binding site. The results in this study suggested that the zinc-finger proteins Sp1 and MAZ could up-regulate the PTEN expression via binding to the sequence from -1035 to -1016 in SMMC-7721 cells and L02 cells.
引文
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