DPC4—一种新的候补肿瘤抑制基因
作者：谷丽君 崔全才 陈杰
单位：中国医学科学院中国协和医科大学北京协和医院 100730
关键词：
诊断病理学杂志000124分类号：R730.1 文献标识码：A
文章编号：1007-8096(2000)01-0058-03 人类肿瘤的发生是一个多因素、多步骤的过程，涉及到多种癌基因的激活和抑癌基因的失活。自1986年首次分离Rb后，已发现10余个抑癌基因，它们以缺失、突变等方式在人类肿瘤的形成中发挥作用。1996年初Kern报道了DPC4(deletedinpancreaticcancerlocus4)—一种新的抑癌基因，现将该基因的研究进展作一综述。
1DPC4基因的发现和结构
, 百拇医药
人类胰腺癌的遗传学改变包括Ki-ras突变、p53突变和p16突变或纯合性缺失，等位基因型研究显示90%的胰腺癌在18q上有杂合性缺失(LOH)。事实上，Bert小组在该区域已克隆了DCC(deletedincoloncancer)基因，但是18q上发生缺失的区域相当大，包含几千个基因，故除DCC外可能还有另外的抑癌基因[1]。Hahn构建了18q缺失图谱和一个近2Mb的物理图谱，并对胰腺癌纯合性缺失的集中部位进行嵌板分析，发现三个重要位点，即DPC1/2(13q12)、p16(DPC3、9p21)和DPC4(18q21.1)。再利用c917-46、外显子扩增、Cdna文库筛选、5’-RACE和BLAST等技术，最终鉴定出一种含有51bp的开放阅读框架表达序列，该序列与人胚脑Cdna文库的杂交鉴定出19个克隆，它们为以前从未报道的DPC4基因。30%的胰腺癌有DPC4纯合性缺失，22%有突变，提示DPC4作为一种候补肿瘤抑制基因，与胰腺癌的发生有极密切的关系[2]。
DPC4基因具有2680bp的转录单位，编码552个氨基酸序列，有11个外显子，10个内含子，其核苷酸序列保存在GenBank的U44378中。(全文见PDF)
, 百拇医药
基金项目：本文受国家教委跨世纪人才基金及国家杰出青年基金资助(编号 39625012)
参考文献：
[1]Hahn SA,Schutte M,Hoque ATMS,et al. DPC4,A Candidate Tumor Sup-pressor Gene at Human Chromosome 18121.1.Science,1996,271:350-353
[2]Hahn SA, Hoque ATMS, Moskaluk CA,et al.Homozygous Deletion Map at 18q21.1 in Pancreatic Cancer.Cancer Res,1996,56:490-494
[3]Moskaluk CA, Kerm SE.Cancer gets Mad:DPC4 and other TGF-β path-way genes in human cancer.Biochimica et Biophysica Acta,1996,1288:M31-M33
, 百拇医药
[4]Liu F, Pouponnot C,Messague J.Dual roke of the Smad4./DPC4 tumor suppressor in TGF-β inducible transcriptional complexes.Genes Dev,1997,11:3157-3167
[5]Atfi A,Bulsine M,Mazars A,et al.Induction of Apoptosis by DPC4, a transcriptional Factor Regulated by Transforming Growth Factorβ-through Stress-activated Protein Kinase/c-Jun N-terminal Kinase (SAPK/JNK)Signaling Pathway.J Biol Chem,1997,272:24731-24734
[6]Gran AM,Zhang L, Wang WX, et al.Induction of p21 wafl Expression and Growth Inhibition by Transfoming Growth Factor β Involve the Tumor Suppressor Gene DPC4 in human Pancreatic Adenocarcinoma Cells.Can-cer Res,1997,57:3929-3934
, http://www.100md.com
[7]Schutte M, Hruban RH, Hedrick L, et al. DPC4.Gene in Various Tumor types,Cancer Res, 1996,56:2527-2530
[8]Moskaluk CA, Hruban RH,Schutte M,et al.Genomic Sequencing of DPC4 in the Analysis of familial Pancreatic Carcinoma.Diagn Mol Pathol,1997,6:85-90
[9]Takagi Y, Kohmura H,Futamura M,et al. Somatic Alterations of the DPC4 Gene in human Colorectal cancers In Vivo. Gastroenterology,1996,111:1369-1372
, 百拇医药
[10]Thiagalingam S, Lengauer C, Leach FS,et al.Evaluation of candidate tu-mour suppressor genes on chromosome 18 in colorectal cancers.Nature Genetics,1996,13:343-346
[11]Lei JY,Zou TT,Shi YQ,et al.Infrequent DPC4 gene mutation in esophageal cancer,gastric cancer and ulcerative colitis-associated neo-plasma.Oncogene,1996,13:2459-2462
[12]Hahn SA,Bartsch D,Schroers A,et al.Mutations of the DPC4/Smad4 Gene in Biliary Tract Carcinoma.Cancer Res,1998,58:1124
, http://www.100md.com
[13]Barrett M,Schutte M,Kern SE,et al.Allelic Loss and Mutational Analy-sis of the DPCA Gene in Esophageal Adenocarcinoma.Cancer Res,1996,56:4351-4353
[14]Nagatake M,Takagi Y,Oaska H,et al.Somatic in Vivo Alterations of the DPC4 Gene at 18q21 in Human Lung Cancers.Cancer Res,1996,56:2718-2720
[15]Kim SK,Fan YH,Papadimitrakopoulou V,et al.DPC4,a Candidate Tu-mor Suppressor Geae,Is Altered Infrequently in Head and Neck Squa-mous Cell Carcinoma.Cancer Res,1996,56:2519-2521
[16]Kong XT,Choi SH,Inoue A,et al.Exprssion and Mutational Analysis of the DCC,DPC4,and MADR2/JV18-1 Genes in Neuroblostoma.Cancer Res,1997,57:3772-3778
收稿日期：1999-05-21
修稿日期：1999-07-05, http://www.100md.com
单位：中国医学科学院中国协和医科大学北京协和医院 100730
关键词：
诊断病理学杂志000124分类号：R730.1 文献标识码：A
文章编号：1007-8096(2000)01-0058-03 人类肿瘤的发生是一个多因素、多步骤的过程，涉及到多种癌基因的激活和抑癌基因的失活。自1986年首次分离Rb后，已发现10余个抑癌基因，它们以缺失、突变等方式在人类肿瘤的形成中发挥作用。1996年初Kern报道了DPC4(deletedinpancreaticcancerlocus4)—一种新的抑癌基因，现将该基因的研究进展作一综述。
1DPC4基因的发现和结构
, 百拇医药
人类胰腺癌的遗传学改变包括Ki-ras突变、p53突变和p16突变或纯合性缺失，等位基因型研究显示90%的胰腺癌在18q上有杂合性缺失(LOH)。事实上，Bert小组在该区域已克隆了DCC(deletedincoloncancer)基因，但是18q上发生缺失的区域相当大，包含几千个基因，故除DCC外可能还有另外的抑癌基因[1]。Hahn构建了18q缺失图谱和一个近2Mb的物理图谱，并对胰腺癌纯合性缺失的集中部位进行嵌板分析，发现三个重要位点，即DPC1/2(13q12)、p16(DPC3、9p21)和DPC4(18q21.1)。再利用c917-46、外显子扩增、Cdna文库筛选、5’-RACE和BLAST等技术，最终鉴定出一种含有51bp的开放阅读框架表达序列，该序列与人胚脑Cdna文库的杂交鉴定出19个克隆，它们为以前从未报道的DPC4基因。30%的胰腺癌有DPC4纯合性缺失，22%有突变，提示DPC4作为一种候补肿瘤抑制基因，与胰腺癌的发生有极密切的关系[2]。
DPC4基因具有2680bp的转录单位，编码552个氨基酸序列，有11个外显子，10个内含子，其核苷酸序列保存在GenBank的U44378中。(全文见PDF)
, 百拇医药
基金项目：本文受国家教委跨世纪人才基金及国家杰出青年基金资助(编号 39625012)
参考文献：
[1]Hahn SA,Schutte M,Hoque ATMS,et al. DPC4,A Candidate Tumor Sup-pressor Gene at Human Chromosome 18121.1.Science,1996,271:350-353
[2]Hahn SA, Hoque ATMS, Moskaluk CA,et al.Homozygous Deletion Map at 18q21.1 in Pancreatic Cancer.Cancer Res,1996,56:490-494
[3]Moskaluk CA, Kerm SE.Cancer gets Mad:DPC4 and other TGF-β path-way genes in human cancer.Biochimica et Biophysica Acta,1996,1288:M31-M33
, 百拇医药
[4]Liu F, Pouponnot C,Messague J.Dual roke of the Smad4./DPC4 tumor suppressor in TGF-β inducible transcriptional complexes.Genes Dev,1997,11:3157-3167
[5]Atfi A,Bulsine M,Mazars A,et al.Induction of Apoptosis by DPC4, a transcriptional Factor Regulated by Transforming Growth Factorβ-through Stress-activated Protein Kinase/c-Jun N-terminal Kinase (SAPK/JNK)Signaling Pathway.J Biol Chem,1997,272:24731-24734
[6]Gran AM,Zhang L, Wang WX, et al.Induction of p21 wafl Expression and Growth Inhibition by Transfoming Growth Factor β Involve the Tumor Suppressor Gene DPC4 in human Pancreatic Adenocarcinoma Cells.Can-cer Res,1997,57:3929-3934
, http://www.100md.com
[7]Schutte M, Hruban RH, Hedrick L, et al. DPC4.Gene in Various Tumor types,Cancer Res, 1996,56:2527-2530
[8]Moskaluk CA, Hruban RH,Schutte M,et al.Genomic Sequencing of DPC4 in the Analysis of familial Pancreatic Carcinoma.Diagn Mol Pathol,1997,6:85-90
[9]Takagi Y, Kohmura H,Futamura M,et al. Somatic Alterations of the DPC4 Gene in human Colorectal cancers In Vivo. Gastroenterology,1996,111:1369-1372
, 百拇医药
[10]Thiagalingam S, Lengauer C, Leach FS,et al.Evaluation of candidate tu-mour suppressor genes on chromosome 18 in colorectal cancers.Nature Genetics,1996,13:343-346
[11]Lei JY,Zou TT,Shi YQ,et al.Infrequent DPC4 gene mutation in esophageal cancer,gastric cancer and ulcerative colitis-associated neo-plasma.Oncogene,1996,13:2459-2462
[12]Hahn SA,Bartsch D,Schroers A,et al.Mutations of the DPC4/Smad4 Gene in Biliary Tract Carcinoma.Cancer Res,1998,58:1124
, http://www.100md.com
[13]Barrett M,Schutte M,Kern SE,et al.Allelic Loss and Mutational Analy-sis of the DPCA Gene in Esophageal Adenocarcinoma.Cancer Res,1996,56:4351-4353
[14]Nagatake M,Takagi Y,Oaska H,et al.Somatic in Vivo Alterations of the DPC4 Gene at 18q21 in Human Lung Cancers.Cancer Res,1996,56:2718-2720
[15]Kim SK,Fan YH,Papadimitrakopoulou V,et al.DPC4,a Candidate Tu-mor Suppressor Geae,Is Altered Infrequently in Head and Neck Squa-mous Cell Carcinoma.Cancer Res,1996,56:2519-2521
[16]Kong XT,Choi SH,Inoue A,et al.Exprssion and Mutational Analysis of the DCC,DPC4,and MADR2/JV18-1 Genes in Neuroblostoma.Cancer Res,1997,57:3772-3778
收稿日期：1999-05-21
修稿日期：1999-07-05, http://www.100md.com