肺癌中PTEN蛋白的表达

蛋白酪氨酸磷酸酶基因 (Ｐｈｏｓｐｈａｔａｓｅａｎｄｔｅｎｓｉｎｈｏｍｏｌｏｇｄｅｌｅｔｅｄｏｎｃｈｒｏｍｏｓｏｍｅｔｅｎ ,ＰＴＥＮ/Ｍｕｔａｔｅｄｉｎｍｕｌｔｉｐｌｅａｄｖａｎｃｅｄｃａｎｃｅｒ1 ,ＭＭＡＣ1 ) [1 5] 是 1 997年发现位于 1 0号染色体 (1 0ｑ2 3)上的一个基因 ,其编码蛋白质即蛋白酪氨酸磷酸酶 (Ｐｒｏｔｅｉｎｔｙｒｏｓｉｎｅｐｈｏｓｐｈａｔａｓｅ)。为了探索ＰＴＥＮ蛋白在肺癌中表达的意义 ,我们用该蛋白的抗体对肺癌进行了免疫组织化学研究 ,现将结果报道于下。一、材料与方法1 材料 :根据ＷＨＯ分类…     

肿瘤抑制基因PTEN／MMAC1／TEP1在肿瘤研究中的进展

肿瘤的发生与多个癌基因及抑癌基因的异常有关。发现和研究癌基因和抑癌基因 ,了解其产物在信号传导通路中的作用 ,将有助于阐明癌变机制 ,及寻找肿瘤药物治疗的靶点。最近 ,由Ｌｉ和Ｓｔｅｃｋ等〔1,2〕 发现的一个肿瘤抑制基因ＰＴＥＮ/ＭＭＡＣ1/ＴＥＰ1逐渐成为肿瘤研究的一个新热点。1　ＰＴＥＮ/ＭＭＡＣ1/ＴＥＰ1基因的发现及命名1997年 3月 ,美国的两个研究小组分别从原发性乳腺癌、胶质母细胞瘤细胞株克隆得到位于 10 ｑ2 3的一种肿瘤抑制基因 ,分别命名为 10号染色体缺失的磷酸酶及张力蛋白同源物 (ｐｈｏｓｐｈａｔａｓｅａｎｄ…     

新的肿瘤抑制基因PTEN

肿瘤在人体内的发生及发展中,随着时间的延长,肿瘤细胞可能会获得越来越多的遗传学改变。研究发现,很多肿瘤有染色体10ｑ23的杂合性丢失,这种改变发生于70%～80%的胶质母细胞瘤及60%的晚期前列腺癌,然而在低度恶性胶质细胞瘤及早期前列腺癌却罕见。1997年,美国3个实验室先后在该位点发现了一个肿瘤抑制基因,分别命名为:ＰＴＥＮ[1](ｐｈｏｓｐｈａｔａｓｅａｎｄｔｅｎｓｉｎｈｏｍｏｌｏｇｕｅｄｅｌｅｔｅｄｏｎｃｈｒｏｍｏｓｏｍｅｔｅｎ),ＭＭＡＣ1[2](ｍｕｔａｔｅｄｉｎｍｕｌｔｉｐｌｅａｄｖａｎｃｅｄｃａｎｃｅｒｓ),ＴＥＰ1[3](…     

子宫内膜癌PTEN及p53蛋白的表达

在子宫内膜癌的研究中已经确定了的、较为常见的分子生物学改变有ｐ5 3突变、Ｋ ｒａｓ突变和微卫星不稳定性 ,大约各占子宫内膜癌的 2 0 %～ 3 0 % [1] 。已发现子宫内膜癌中ＰＴＥＮ抑癌基因 (ｐｈｏｓｐｈａｔａｓｅａｎｄｔｅｎｓｉｎｈｏｍｏｌｏｇｄｅｌｅｔｅｄｏｎｃｈｒｏｍｏｓｏｍｅｔｅｎ)突变率为 3 2 %～ 5 5 % ,是迄今为止子宫内膜癌中所发现的突变率最高的基因改变[2 4 ] 。我们拟通过观察子宫内膜癌ＰＴＥＮ及ｐ5 3蛋白表达的情况来探讨其与子宫内膜癌的发生、发展和预后的关系。一、材料和方法80例子宫内膜癌标本选自北…     

环氧-二十碳三烯酸：细胞内信号转导通路

花生四烯酸 (ａｒａｃｈｉｏｎｄｉｃａｃｉｄ ,ＡＡ)细胞色素Ｐ4 5 0单氧化酶代谢产物是环氧 -二十碳三烯酸 (ｅｐｏｘｙｅ ｉｃｏｓａｔｒｉｅｎｏｉｃａｃｉｄ ,ＥＥＴｓ) ,可分为 :5 ,6 -ＥＥＴ ;8,9-ＥＥＴ ;11,12 -ＥＥＴ和 14,15 -ＥＥＴ[1] 。ＥＥＴｓ作为内皮衍生性超极化因子 (ｅｎｄｏｔｈｅｌｉａｌｄｅｒｉｖｅｄｈｙｐｅｒｐｏｒｌａｒｉｎｇｆａｃｔｏｒ ,ＥＤＨＦ) ,调节多种血管张力 ;抑制血小板的聚集 ;促进有丝分裂等。近来 ,有关ＥＥＴｓ的作用机制尤其在信号转导方面的作用引起了重视。近来的研究表明 ,ＥＥＴｓ通过影…     

直肠癌全直肠系膜切除术的解剖学基础

由于低位直肠癌行治愈性切除后存在着较高的局部复发率及术后性功能和泌尿功能的障碍 ,因此 ,在世界范围内有关直肠癌的治疗一直是困绕外科界的一大棘手问题。随着Ｈｅａｌｄ[1] 等在 1982年提出全直肠系膜切除术 (ｔｏｔａｌｍｅｓｏｒｅｃｔａｌｅｘｃｉ ｓｉｏｎ ,ＴＭＥ)或称直肠周围系膜全切除术 (ｃｏｍｐｌｅｔｅｃｉｒｃｕｍｆｅｒｅｎｔｉａｌｍｅｓｏｒｅｃｔａｌｅｘｃｉｓｉｏｎ ,ＣＣＭＥ)这一新技术以来 ,上述问题才得以改观[2～ 5] ,目前 ,ＴＭＥ正得到越来越广泛的认可和应用 ,并已成为直肠癌手术的“金标准”。本文将ＴＭ…     

超广谱β-内酰胺酶基因分型的初步研究

按质粒所携带编码基因同源性的不同 ,将超广谱 β 内酰胺酶 (Ｅｘｔｅｎｄｅｄｓｐｅｃ ｔｒｕｍ β ｌａｃｔａｍａｓｅｓ,ＥＳＢＬｓ)分为 4类 ,即ＴＥＭ型、ＳＨＶ型、ＴＥＭ ＳＨＶ混合型和非ＴＥＭ 非ＳＨＶ型 (包括ＰＥＲ、ＴＯＨＯ、ＣＴＸ Ｍ、ＯＸＡ型等 )。本文报告绍兴地区产ＥＳＢＬｓ细菌基因分型的初步结果。临床标本分离、并经纸片扩散法确证为产ＥＳＢＬｓ的细菌 42株 (其中大肠埃希菌 2 6株 ,肺炎克雷伯菌 16株 )。用ＰＣＲ进行酶基因分型。ＰＣＲ扩增引物 ,根据ＴＥＭ 1和ＳＨＶ 1编码基因序列设计 ,ＴＥＭ引物序列分别为…     

肝细胞肝癌组织中PTEN和p53蛋白的表达

ＰＴＥＮ又名ＭＭＡＣ1或ＴＥＰ1,其表达产物参与细胞骨架重组及由此引发信号传导并影响细胞转移。目前 ,有关ＰＴＥＮ的研究多集中于基因的突变和缺失 ,而对ＰＴＥＮ基因蛋白的表达则研究极少 ,尤其是肝癌组织中ＰＴＥＮ蛋白的表达研究 ,国内外尚未见文献报道。为此 ,我们应用免疫组化技术对肝细胞肝癌组织中抑癌基因ＰＴＥＮ及 ｐ5 3蛋白表达情况进行了研究 ,以探讨两种抑癌基因在肝细胞肝癌发生发展中的作用及其临床病理意义。1　材料与方法1.1　材料　 4 1例肝癌及癌旁组织为 1996～ 2 0 0 0年邮电总医院病理科存档外科手术标本。年龄 2…     

MMN与老年人及阿尔茨海默病的相关性研究进展

一、ＭＭＮ的概念与基本性质失匹配负波 (ｍｉｓｍａｔｃｈｎｅｇａｔｉｖｉｔｙ ,ＭＭＮ)是一种内源性事件相关电位(ｅｖｅｎｔ-ｒｅｌａｔｅｄｐｏｔｅｎｔｉａｌ,ＥＲＰ)成分 ,出现在刺激后 10 0 -2 0 0ｍｓ[1 ] 。 1978年由Ｎ¨ａ¨ａｔ¨ａｎｅｎ等[2 ] 首先观察到 ,运用听觉ｏｄｄｂａｌｌ实验模式 ,在标准声音刺激中随机插入偏差刺激 ,分别在被试双耳中呈现 ,无论注意与否 ,在约 2 5 0ｍｓ内偏差刺激皆比标准刺激引起更高负波 ,若以偏差刺激引起的ＥＲＰ减去标准刺激引起的ＥＲＰ ,观察此差异波 ,则可见到在约10 0ｍｓ至 2 5 0ｍｓ之…     

CYP1A1、NAT2基因多态性与帕金森病的关系

为探讨代谢酶基因多态与帕金森病 (ＰＤ)易患性的关系 ,我们应用ＰＣＲ ＲＦＬＰ、ＡＳＡ和自动实时荧光Ｌｉｇｈｔ Ｃｙｃｌｅｒ技术对 90例ＰＤ患者的ＣＹＰ1Ａ1ＭｓｐＩ基因型和第 7外显子4 889位异亮氨酸 (Ｉｌｅ) 缬氨酸 (Ｖａｌ)基因型及Ｎ 乙酰基转移酶 2(ＮＡＴ 2 )基因 4个多态 :第 4 81位点的 (Ｃ→Ｔ) [ＮＡＴ 2 5Ａ];第5 90位点的 (Ｇ→Ａ) [ＮＡＴ2 6Ａ];第 85 7位点的 (Ｇ→Ａ)[ＮＡＴ2 7Ａ/Ｂ]和第 191位点的 (Ｇ→Ａ) [ＮＡＴ2 14Ａ]进行检测和分析1　对象和方法1.1　对象　ＰＤ患者 90例 (早发ＰＤ患者 4 2例 ,男 2 2…     

头颈部鳞癌中抑癌基因PTEN的研究进展

The FTEN, having a dual specificity phosphatase activity, is the first tumor suppressor gene that possess phosphatase activity hitherto. Many researches have suggested that FTEN play a major role in the tumorgenesis. In clinical, the head and neck squamous cell carcinoma(HNSCC) is one of the most common ma-lignant tumors. In this review, advances in the research of FTEN and the relationship between the PTEN and HNSCC are discussed.     

PTEN as a Unique Promising Therapeutic Target for Occupational Asthma

The tumor suppressor phosphatase and tensin homologue deleted on chromosome ten (PTEN) dephophorylates phosphatidylinositol 3,4,5-triphosphate (PIP3) and is a key negative regulator of phosphoinositide kinase-3 (PI3K) signaling pathway. PTEN also suppresses cellular motility through mechanisms that may be partially independent of phosphatase activity. PTEN is one of the most commonly lost tumor suppressors in human cancers, and its down-regulation is also implicated in several other diseases including airway inflammatory diseases. There is increasing evidence regarding the protective effects of PTEN on the bronchial asthma which is induced by complex signaling networks. Very recently, as for the occupational asthma (OA) with considerable controversy for its pathobiologic mechanisms, PTEN has been considered as a key molecule which is capable of protecting toluene diisocyanate (TDI)-induced asthma, suggesting that PTEN is located at switching point of various molecular signals in OA. Knowledge of the mechanisms of PTEN regulation/function could direct to the pharmacological manipulation of PTEN. This article reviews the latest knowledge and studies on the roles and mechanisms of PTEN in OA.     

A comprehensive functional analysis of PTEN mutations: implications in tumor- and autism-related syndromes

The PTEN (phosphatase and tensin homolog) phosphatase is unique in mammals in terms of its tumor suppressor activity, exerted by dephosphorylation of the lipid second messenger PIP(3) (phosphatidylinositol 3,4,5-trisphosphate), which activates the phosphoinositide 3-kinase/Akt/mTOR (mammalian target of rapamycin) oncogenic pathway. Loss-of-function mutations in the PTEN gene are frequent in human cancer and in the germline of patients with PTEN hamartoma tumor-related syndromes (PHTSs). In addition, PTEN is mutated in patients with autism spectrum disorders (ASDs), although no functional information on these mutations is available. Here, we report a comprehensive in vivo functional analysis of human PTEN using a heterologous yeast reconstitution system. Ala-scanning mutagenesis at the catalytic loops of PTEN outlined the critical role of residues within the P-catalytic loop for PIP(3) phosphatase activity in vivo. PTEN mutations that mimic the P-catalytic loop of mammalian PTEN-like proteins (TPTE, TPIP, tensins and auxilins) affected PTEN function variably, whereas tumor- or PHTS-associated mutations targeting the PTEN P-loop produced complete loss of function. Conversely, Ala-substitutions, as well as tumor-related mutations at the WPD- and TI-catalytic loops, displayed partial activity in many cases. Interestingly, a tumor-related D92N mutation was partially active, supporting the notion that the PTEN Asp92 residue might not function as the catalytic general acid. The analysis of a panel of ASD-associated hereditary PTEN mutations revealed that most of them did not substantially abrogate PTEN activity in vivo, whereas most of PHTS-associated mutations did. Our findings reveal distinctive functional patterns among PTEN mutations found in tumors and in the germline of PHTS and ASD patients, which could be relevant for therapy.     

PTEN as a unique promising therapeutic target for occupational asthma

The tumor suppressor phosphatase and tensin homologue deleted on chromosome ten (PTEN) dephophorylates phosphatidylinositol 3,4,5-triphosphate (PIP3) and is a key negative regulator of phosphoinositide kinase-3 (PI3K) signaling pathway. PTEN also suppresses cellular motility through mechanisms that may be partially independent of phosphatase activity. PTEN is one of the most commonly lost tumor suppressors in human cancers, and its down-regulation is also implicated in several other diseases including airway inflammatory diseases. There is increasing evidence regarding the protective effects of PTEN on the bronchial asthma which is induced by complex signaling networks. Very recently, as for the occupational asthma (OA) with considerable controversy for its pathobiologic mechanisms, PTEN has been considered as a key molecule which is capable of protecting toluene diisocyanate (TDI)-induced asthma, suggesting that PTEN is located at switching point of various molecular signals in OA. Knowledge of the mechanisms of PTEN regulation/function could direct to the pharmacological manipulation of PTEN. This article reviews the latest knowledge and studies on the roles and mechanisms of PTEN in OA.     

Analysis of genetic and epigenetic alterations of the PTEN gene in gastric cancer

The PTEN tumor suppressor gene on 10q23.3, responsible for the Cowden and Bannayan-Zonana syndromes, encodes a dual-specificity phosphatase able to dephosphorylate both tyrosine phosphate and serine/threonine phosphate residues. Mutational inactivation of PTEN has been reported in various malignancies, including endometrial cancers, ovarian cancers, and glioblastomas. In this study, we investigated PTEN gene mutations in 10 gastric cancer cell lines and 58 primary gastric cancers by polymerase chain reaction single strand conformation polymorphism (PCR-SSCP). Hypermethylation of promoter region CpG islands, an alternative mechanism of gene inactivation to coding region mutations, was also evaluated by methylation specific PCR (MSP). Only one (1.7%) of the 58 primary tumors carried a somatic 5-bp deletion in intron 7 of PTEN, which did not alter the mRNA sequence, and no mutations were detected in any of the cell lines. Similar levels of PTEN mRNA expression were observed in all cell lines and primary tumors studied by RT-PCR, and PTEN promoter CpG islands remained unmethylated. Therefore, we conclude that PTEN does not participate in gastric carcinogenesis as a tumor suppressor gene.     

磷脂酰肌醇生物合成通路中的新肿瘤抑制基因INPP4B

磷脂酰肌醇信号通路参与许多的癌症和其他疾病发生发展。该通路中存在多个肿瘤相关基因,其中抑癌基因PTEN、癌基因 PI3K是被广泛研究的两个基因。最近这条通路中的另一个磷脂酰磷酸酶,磷脂酰肌醇4-磷酸酶Ⅱ型（INPP4B）,被证实是一个潜在的肿瘤抑制基因,其在前列腺癌、乳腺癌中低表达或突变,与该疾病的发生、预后相关。该文重点阐述了 INPP4B的分子结构和功能,及其介导的 Akt-mTOR 信号传导通路,与 PTEN 的协同作用及与几种肿瘤的相关性,并探讨 INPP4B 在细胞核内维护基因组稳定性的潜在作用。总之,对 INPP4B的深入研究不仅为磷脂酰肌醇信号调控肿瘤发生提供了新机制,而且为抗肿瘤药物研究提供了有价值的分子靶点。     

PTEN coordinates G(1) arrest by down-regulating cyclin D1 via its protein phosphatase activity and up-regulating p27 via its lipid phosphatase activity in a breast cancer model

The tumour suppressor gene PTEN/MMAC1/TEP1 encodes a dual-specificity phosphatase that recognizes phosphatidylinositol-3,4,5-triphosphate and protein substrates. We have shown previously that over-expression of PTEN in a tetracycline-controlled inducible system blocks cell cycle progression and induces apoptosis in MCF-7 breast cancer cells. Here, we demonstrate that over-expression of wild-type PTEN leads to the suppression of cell growth through the blockade of cell cycle progression, an increase in the abundance of p27, a decrease in the protein levels of cyclin D1 and the inhibition of Akt phosphorylation. In contrast, expression of the phosphatase-dead mutant, C124S, promotes cell growth and has the opposite effect on the abundance of p27, cyclin D1 levels and the phosphorylation of Akt. The G129E mutant, which does not have lipid phosphatase activity but retains protein phosphatase activity, behaves like C124S except that the former causes decreases in cyclin D1 levels similar to wild-type PTEN. Therefore, PTEN exerts its growth suppression through lipid phosphatase-dependent and independent activities and most likely, via the coordinate effect of both protein phosphatase and lipid phosphatase activities. Addition of either estrogen or insulin abrogates PTEN-mediated up-regulation of p27 and partially blocks PTEN-mediated growth suppression, whereas the combination of estrogen and insulin eliminates the alterations of p27 and cyclin D1 and completely blocks PTEN-mediated growth suppression. Our findings demonstrate that PTEN blocks cell cycle progression differentially through down-regulating the positive cell cycle regulator, cyclin D1, by its protein phosphatase activity, and up-regulating the negative cell cycle regulator, p27, by its lipid phosphatase activity.