自噬相关基因Beclin 1在喉鳞状细胞癌中的表达及意义
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摘要
喉癌是头颈部的常见的恶性肿瘤,其发病率逐年上升,发病机制不甚明确。从基因水平探索肿瘤的发生、发展、转移及治疗是目前研究的热点。
程序性细胞死亡(PCD)是受基因控制的细胞死亡方式。目前,人们对程序性死亡的研究主要集中在两大类:由caspase介导的细胞凋亡(1型细胞死亡)和非caspase介导的白体吞噬(2型细胞死亡)。细胞进行自体吞噬时,细胞质中的线粒体等细胞器首先被称为“隔离膜”的囊泡所包被,然后被运送到溶酶体/空泡中降解。研究表明自体吞噬能抑制肿瘤细胞生长。
Beclin 1与Bcl-2家族有关,其位于染色体17q21,是自噬重要的正调节因子。有文献报道染色体17q21的等位基因缺失在卵巢癌中高达75%,乳腺癌为50%,前列腺癌中为40%。研究表明Beclin 1杂合性缺失是细胞发生恶性转化的原因之一,是一个候选的肿瘤抑制基因。
目的:本实验的目的是探讨Beclin 1在喉鳞状细胞癌中的表达及与临床分期、肿瘤发生部位、病理分级和淋巴结转移等特征之间的关系。
方法:应用免疫组织化学SP法,检测Beclin 1在38例喉癌及20例癌旁组织标本中的表达.利用SPSS统计学软件及X~2检验分析其与各临床病理参数之间的关系。
结果
1.Beclin 1在喉鳞状细胞癌组织和癌旁组织中的表达率分别为28.95%(11/38)和70%(14/20),癌组织中的表达率明显低于癌旁组织,两组间有显著差异(p＜0.01)。
2.Beclin 1在高分化鳞癌组织中的表达率为35%(7/20),在中低分化鳞癌中的表达率为22.22%(4/18),两组之间的差异无显著性(p＞0.05)。
3.有淋巴结转移的癌组织和无淋巴结转移的癌组织中的Beclin 1的表达率分别为12.5%(2/16)和40.9%(9/22),两组有显著差异(p＜0.05)。
4.临床分期Ⅰ-Ⅱ期喉癌组织中Beclin 1的表达率为40%(6/15),而在Ⅲ-Ⅳ期喉癌组织中为21.74%(5/23)两者之间比较无显著性差异(p＞0.05)。
5.Beclin 1在声门上型喉癌组织中的表达率为23.08%(3/13),在声门型喉癌组织中表达率为32%(8/25),两者之间的差异无显著性(p＞0.05)。
结论:研究表明Beclin 1在喉鳞状细胞癌中的表达明显低于癌旁组织,在有淋巴结转移的喉癌组织中Beclin 1的表达明显低于无淋巴结转移组织。说明Beclin 1的表达异常与喉鳞癌的发生和转移有关。
Laryngeal carcinoma is one of most common malignant neoplasm in head and neck.In recent years,the morbidity of laryngocarcinoma appears an increasing tendency.It has become special focus to investigate the oncogensis,developing,metastasis and management of the tumor from the molecule level.
Programmed cell death(PCD)is an essential and highly orchestrated process.Two major types of PCD have been distinguished:the caspase-mediated process of apoptosis(type 1 cell death)and the caspase-independent process involving autophagy(type 2 cell death). Autophagy is an evolutionary conserved lysosomal pathway involved in the turnover of long lived proteins and organelles.Autophagy starts with the formation of a multilayer membrane-bound autophagosome that sequesters fractions of the cytoplasm.Autophagy has increased inhibition of tumor cell growth,in a variety of tumor cell lines in the low-level expression.
Beclin 1,identified as a Bcl-2 interacting protein,is known to enhance autophagy.The human beclin-1 gene has been mapped to a region of chromosome 17q21 that is monoallelically deleted in up to 75% of ovarian cancers,50%of breast cancers,and 40%of prostate cancers. Based on these observations,it demonstratethat Beclin 1 is a novel mechanism of cell-growth control and tumor suppression.Beclin-1 is a candidate tumor-suppressor gene.
Objective:The aim of this investigation is to study the expression of Beclin-1 in laryngeal squamous cell carcinoma and normal tissues adjacent to cancer,and study the correlation between its expression and clinical-pathological parameters of primary laryngeal squamous cell carcinoma.
Methods:Expression level of Beclin 1 was detected in 38 human laryngeal cancer samples and 20 normal tissues adjacent to cancer respectively,and their correlation with tumor sit,tumor grade,lymph node metastasis and clinical stage was studied by immunohistochemistry(IHC)methods.The statistical evaluation was performed with SPSS software for windows.
Results:
1.The expression of Beclin 1 in LSCC are obviously lower than that in normal tissues adjacent to cancer and there was statistical significance(P＜0.01).
2.The positive rate of Beclin 1 in well-differentiated samples and poorly differentiated samples were 35%(7/20)and 22.22%(4/18) respectively,there was no statistical significance(P＞0.05).
3.The expression of Beclin 1 in LSCC with lymph node metastasis were obviously lower than that without,and there was statistical significance(P＜0.05).
4.The positive rate of Beclin 1 inⅠ-Ⅱstages andⅢ-Ⅳstages were 40%(6/15)and 21.74%(5/23)respectively,there was no statistical significance(P＞0.05).
5.The positive rate of Beclin 1 in supra-glottic carcinoma and glottic carcinoma were 23.08%(3/13)and 32%(8/25)respectively.There was no statistical significance(P＞0.05).
Conclusion:The expression of Beclin-1 in LSCC are obviously lower than that in normal tissues adjacent to cancer and the expression of Beclin 1 in LSCC with lymph node metastasis were obviously lower than that without,which showed Beclin-1 had a close relationship with LSCC and its metastasis.The study of relationship between Beclin 1 and laryngeal carcinoma reminds us a new gene therapy of laryngeal carcinoma by strengthen the function of Beclin 1.
程序性细胞死亡(PCD)是受基因控制的细胞死亡方式。目前,人们对程序性死亡的研究主要集中在两大类:由caspase介导的细胞凋亡(1型细胞死亡)和非caspase介导的白体吞噬(2型细胞死亡)。细胞进行自体吞噬时,细胞质中的线粒体等细胞器首先被称为“隔离膜”的囊泡所包被,然后被运送到溶酶体/空泡中降解。研究表明自体吞噬能抑制肿瘤细胞生长。
Beclin 1与Bcl-2家族有关,其位于染色体17q21,是自噬重要的正调节因子。有文献报道染色体17q21的等位基因缺失在卵巢癌中高达75%,乳腺癌为50%,前列腺癌中为40%。研究表明Beclin 1杂合性缺失是细胞发生恶性转化的原因之一,是一个候选的肿瘤抑制基因。
目的:本实验的目的是探讨Beclin 1在喉鳞状细胞癌中的表达及与临床分期、肿瘤发生部位、病理分级和淋巴结转移等特征之间的关系。
方法:应用免疫组织化学SP法,检测Beclin 1在38例喉癌及20例癌旁组织标本中的表达.利用SPSS统计学软件及X~2检验分析其与各临床病理参数之间的关系。
结果
1.Beclin 1在喉鳞状细胞癌组织和癌旁组织中的表达率分别为28.95%(11/38)和70%(14/20),癌组织中的表达率明显低于癌旁组织,两组间有显著差异(p＜0.01)。
2.Beclin 1在高分化鳞癌组织中的表达率为35%(7/20),在中低分化鳞癌中的表达率为22.22%(4/18),两组之间的差异无显著性(p＞0.05)。
3.有淋巴结转移的癌组织和无淋巴结转移的癌组织中的Beclin 1的表达率分别为12.5%(2/16)和40.9%(9/22),两组有显著差异(p＜0.05)。
4.临床分期Ⅰ-Ⅱ期喉癌组织中Beclin 1的表达率为40%(6/15),而在Ⅲ-Ⅳ期喉癌组织中为21.74%(5/23)两者之间比较无显著性差异(p＞0.05)。
5.Beclin 1在声门上型喉癌组织中的表达率为23.08%(3/13),在声门型喉癌组织中表达率为32%(8/25),两者之间的差异无显著性(p＞0.05)。
结论:研究表明Beclin 1在喉鳞状细胞癌中的表达明显低于癌旁组织,在有淋巴结转移的喉癌组织中Beclin 1的表达明显低于无淋巴结转移组织。说明Beclin 1的表达异常与喉鳞癌的发生和转移有关。
Laryngeal carcinoma is one of most common malignant neoplasm in head and neck.In recent years,the morbidity of laryngocarcinoma appears an increasing tendency.It has become special focus to investigate the oncogensis,developing,metastasis and management of the tumor from the molecule level.
Programmed cell death(PCD)is an essential and highly orchestrated process.Two major types of PCD have been distinguished:the caspase-mediated process of apoptosis(type 1 cell death)and the caspase-independent process involving autophagy(type 2 cell death). Autophagy is an evolutionary conserved lysosomal pathway involved in the turnover of long lived proteins and organelles.Autophagy starts with the formation of a multilayer membrane-bound autophagosome that sequesters fractions of the cytoplasm.Autophagy has increased inhibition of tumor cell growth,in a variety of tumor cell lines in the low-level expression.
Beclin 1,identified as a Bcl-2 interacting protein,is known to enhance autophagy.The human beclin-1 gene has been mapped to a region of chromosome 17q21 that is monoallelically deleted in up to 75% of ovarian cancers,50%of breast cancers,and 40%of prostate cancers. Based on these observations,it demonstratethat Beclin 1 is a novel mechanism of cell-growth control and tumor suppression.Beclin-1 is a candidate tumor-suppressor gene.
Objective:The aim of this investigation is to study the expression of Beclin-1 in laryngeal squamous cell carcinoma and normal tissues adjacent to cancer,and study the correlation between its expression and clinical-pathological parameters of primary laryngeal squamous cell carcinoma.
Methods:Expression level of Beclin 1 was detected in 38 human laryngeal cancer samples and 20 normal tissues adjacent to cancer respectively,and their correlation with tumor sit,tumor grade,lymph node metastasis and clinical stage was studied by immunohistochemistry(IHC)methods.The statistical evaluation was performed with SPSS software for windows.
Results:
1.The expression of Beclin 1 in LSCC are obviously lower than that in normal tissues adjacent to cancer and there was statistical significance(P＜0.01).
2.The positive rate of Beclin 1 in well-differentiated samples and poorly differentiated samples were 35%(7/20)and 22.22%(4/18) respectively,there was no statistical significance(P＞0.05).
3.The expression of Beclin 1 in LSCC with lymph node metastasis were obviously lower than that without,and there was statistical significance(P＜0.05).
4.The positive rate of Beclin 1 inⅠ-Ⅱstages andⅢ-Ⅳstages were 40%(6/15)and 21.74%(5/23)respectively,there was no statistical significance(P＞0.05).
5.The positive rate of Beclin 1 in supra-glottic carcinoma and glottic carcinoma were 23.08%(3/13)and 32%(8/25)respectively.There was no statistical significance(P＞0.05).
Conclusion:The expression of Beclin-1 in LSCC are obviously lower than that in normal tissues adjacent to cancer and the expression of Beclin 1 in LSCC with lymph node metastasis were obviously lower than that without,which showed Beclin-1 had a close relationship with LSCC and its metastasis.The study of relationship between Beclin 1 and laryngeal carcinoma reminds us a new gene therapy of laryngeal carcinoma by strengthen the function of Beclin 1.
引文
[1] Lock shin RA, Zakeri Z. Apoptosis, autophagy, andmore. Int J Biochem Cell Biol, 2004; 36 (12): 2405-2419
[2] Arico S, Petiot A , Bauvy C, et al. The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinosito 13 kinase /protein kinase B pathway. Biol Chem, 2001; 276 (38): 35243-35246.
[3] Lock shin RA , Zakeri Z. Caspase-independent cell death. CurrOp in Cell Bio 1, 2002; 14 (6): 727-733
[4] Liang XH, Kleeman L K, Jiang HH, et al. Protection against fatal Sindbid virus encephalitis by Beclin 1, a novel Bcl-2 interacting protein. Viro 1, 1998; 72: 8586-8596.
[5] Kihara A , Kabeya Y, Ohsumi Y, et al. Beclin 1 phosphatidylinosito 13kinase complex function at the transgolginetwork. EMBO , 2001; 2 (4): 330-335.
[6] Liang XH, Jackson S, Seaman M , et al. Induction of autophagy and inhibition of tumorigenesis by Beclin 1. Nature, 1999; 402 (6762): 672-676
[7] Aita VM ,Liang XH,Murty W , et al. Cloning and genomic organization of Beclin 1, a candidate tumor suppressor gene on chromosome 17q21. Genomics, 1999; 59 (1): 59-65.
[8] Daisuke Furuya, Naoki Tsuji, Atsuhito Yagihashi, Naoki Watanabe. (2005) Beclinl augmented cis-diamminedichloroplatinum induced apoptosis via enhancing caspase-9 activity. Exp Cell Res 307: 26-40.
[9] Nara A , Mizushima N , Yamamoto A , et al. SKD1 AAA AT-Pase-dependent endosomal transport is involved in autolysosomeformation. Cell StructFunct, 2002, 27 : 29-37.
[10] Daniel J K. The molecular machinery of autophagy: unanswered questions. Journal of Cell Science,2005,118(1): 7—18.
[11] Petiot A , OgierDenis E, Blommaart EFC, et al. Distinct classes of phosphatidylinosito 13kinases are involved in signaling pathways that control macroautophagy in HT-29 cells.J Bio l Chem,2000;275(2):992-998.
[12]Klionsky DJ,Emr SD.Autophagy as a regulated pathway of cellular degradation.Science,2000,290:1717-1721.
[13]Futreal PA,Liu Q,Shattuck Eidens D,et al.Beclin 1 mutations in primary breast and ovarian carcinomas.Science,1994;266(5182):120-122.
[14]Liang XH,Kleeman L K,Jiang HH,et al.Protection against fatal Sindbid virus encephalitis by Beclin,a novelBcl-2 interacting protein.Viro l,1998;72:8586-8596.
[15]Meijer AJ and Codogno P.(2004)Regulation and role of autophagy in mammalian cells.Int J Biochem Cell Biol 36:2445-2462.
[16]Scott R C,Schuldiner O,Neufeld T P.Neufeld.Role and regulation of starvation-induced autophagy in the drosophilafat body[J].Dev Cell,2004,7(2):167-178.
[17]王赞宏,彭芝兰,段振玲,闰乃红自噬基因Beclin 1 shRNA表达质粒的构建及其对宫颈癌细胞HeLa生长的作用J Sichuan Univ(Med Sci Edi)2007;38(2):181 185
[18]Tassa A,Roux MP,Attaix D,et al.Class Ⅲphosphoinositide 3-kinase-Beclinl complex mediates the amino acid-dependent regulation of autophagy in C2C12myotubes Biochem J,2003,376:577-586
[19]Futreal PA,L iu Q,Shattuck Eidens D,et al.BRCA 1 mutations in primary breast and ovarian carcinomas.Science,1994;266(5182):120-122.
[20]Liang X H,Jackson S,Seaman M,et al.Induction of autophagy and inhibition of tumorigenesis by Beclin 1.Nature,1999,402(6762):672-676
[21]Yue Z,J in S,Yang C,et al.Beclin 1,an autophagy gene essential for early embryonic development,is a haplo insufficient tumor suppressor.Proc Natl Acad Sci USA,2003;100(25):15077-15082
[22]上皮性卵巢癌中自噬基因Beclin 1的表达及其调控相关信号传导途径的研究J Sichuan Un iv(Med Sc i Edi)2007;38(2):239 242
[23]Yue Z,J in S,Yang C,et al.Beclin 1,an autophagy gene essential for early embryonic development,is a haplo insufficient tumor suppressor.Proc Natl Acad Sci USA,2003;100(25):15077-15082.
[24]Qu X,Yu J,Bhagat G,et aI.Promotion of tumorigenesis by heterozygous disruption of the Beclin 1 autophagy gene.Clin Invest,2003;112(12):180-220
[25]Qu X,Yu J,Bhagat G,et al.Promotion of tumorigenesis by heterozygous disruption of the Beclin 1 autophagy gene.Clin Invest,2003;112(12):1800-1820
[26]Scarlatti F,Bauvy C,VentrutiA,et al.Ceramidemediated macroautophagy involves inhibition of protein kinase B and upregulation of Beclin 1[J].J Biol Chem,2004,279(18):18384-18391
[27]QianW,Liu J,J in J,et al.Arsenic trioxide induces not only apoptosis but also autophagic cell death in leukemia cell lines via upregulation of Beclin 1[J].Leuk Res,2007,31(3):329-339
[28]EI-DeryWS,Tokino Y,Velculescu VE,et al.WAF1,a potentialmediator of p53 tumor suppression[J].Cell,1993,75:817-825
[29]Rognard J,Clark A S,N i Y,et al.PKB/protein kinase B is constitutively active in nonsmall cell lung cancer cells and promotes cellular survival and resistance to,chemotherapy and radiation[J].Cancer Res,2001,61(4):3986-3997
[30]王赞宏,彭芝兰,段振玲,闫乃红 自噬基因Beclin 1 shRNA表达质粒的构建及其对宫颈癌细胞HeLa生长的作用J Sichuan Univ(Med Sci Edi)2007;38(2):181 185
[31]Chau YP,Lin SY,Chen JH et al.Endostatin induces autophagic cell death in EAhy926 human endothelial cells[J].Histol Histopathol,2003,18(3):715-726.
[32]Wen S,Stolarov J,Myers MP et al.PTEN controls humor-induced angiogenesis,Proc Natl Acad Sci USA,2001:98:4622-4627
[33]王赞宏,彭芝兰,段振玲,刘辉自噬基因B eclin 1在宫颈鳞癌中的蛋白表达及其临床意义],J Sichuan Univ(Med Sci Edi)2006;37(6):860 863
[34]Gomez-Santos C,Ferrer I,Santidrian A.F,Barrachina M,Gil J,Ambrosio S.(2003)Dopamine induces autophagic cell death and alpha-synuclein increase in human neuroblastoma SH-SY5Y cells.J Neurosci Res 73(3):341-350.
[35]Hoyer HansenM,Bastholm L,Mathiasen IS et al.Vitamin D analog EB1089triggers dramatic lysosomal changes and Beclin 1 mediated autophagic cell death [J].Cell Death Differ,2005,12(10):1297-309.
[36]Hawkins CJ,Vaux DL.Analysis of the role of Bcl-2 in apoptosis.Iinmunol Rev,1994;141:127
[37]Gorski SM,Chittaranjan S,Pleasance ED,et al.A SAGE approach to discovery of genes involved in autophagic cell death.Curr Biol,2003,13:358-363
[38]N g G,Huang J.The significance of autophagy in cancer.Molecular Carcinogenesis,2005;43(4):183-187
[39]Xue L,Fletcher GC,Tolkovsky AM.Autophagy is activated by apoptotic signaling in sympathetic neurons:an alternative mechanism of death execution.Mol Cell Neurosci,1999,14:180-198
[40]Chittenden T,Harrington EA.Introduction of apoptosis by Bcl-2 homologue BAK.Nature,1999;389:733-736
[41]Boya P,Gonzalez-Polo RA,Casares N et al.(2005)Inhibition of macroautophagy triggers apoptosis.Mol Cell Biol 25(3):1025-1040.
[42]Yanagisawa H,Miyashita T,Nakano Y,et al.Beclin 1,a transmembrane protein interacting with Bcl-2/Bcl-xL,induces a caspase independent autophagic cell death.Cell Death Differ,2003,10:798-807
[43]Ng G,Huang J.The Significance of autophagy in cancer[J].MolCarcinog,2005,43(4):183-187
[44]Pattingre S,L evine B.Bcl-2 inhibition of autophagy:a new route to cancer.Cancer Research,2006;66(6):2885-2888
[45]Liang XH,Jack son S,Seaman M,et al.Induction of autophagy and inhibition of tumorigenesis by Beclin 1.Nature,1999;402(6762):672-676
[46]李家喜,王锦玲,郭志祥,刘振声喉癌组织中抗凋亡基因Bcl-2蛋白的表达及临床相关性研究Med J Ch in PLA Vol 22 No 2 April 1997 110-112
[47]张敏燕,张正民,韩仲明等调亡相关基因Bcl-2、BAX蛋白在喉鳞癌组织中的表达及其临床意义,耳鼻咽喉头颈外科 2001;8(1)27-30
[48]Shintani T and Klionsky DJ.(2004)Autophagy in health and disease:a double-edged sword. Science (306):990-995
[49] Marino G and Lopez-Otin C. (2004) Autophagy: molecular mechanisms, physiological functions and relevance in human pathology. Cell Mol Life Sci 61(12):1439-1454.
[50] Alva AS, Gultekin SH, Baehrecke EH. (2004) Autophagy in human tumour cell survival or death? Cell Death Differ 11(9): 1046-1048
[51] Paglin S, Hollister T, Delohery T et al. (2001) A novel response of cancer cells to radiation involves autophagy and formation of acidic vesicles. Cancer Res 61:439-444
[52] Joyce JA ,Baruch A ,Chehade K,et al. [J ]. Cancer Cell ,2004,5 (5) :443-453. Florez-McClure ML, Linseman DA, Heidenreich KA et al. (2004) The p75 neurotrophin receptor can induce autophagy and death of cerebellar Purkinje neurons. J Neurosci 24(19): 4498-4509
[53] Bauvy C,Gane P,Arico S et al.Autophagy delays sulindac sulphide-induced apoptosis in the human intestinal colon cancer cell line HT-29.Exp Cell Res,2001;268:139-49
[54] Florez-McClure ML, Linseman DA, Heidenreich KA et al. (2004) The p75 neurotrophin receptor can induce autophagy and death of cerebellar Purkinje neurons. J Neurosci 24(19): 4498-4509
[1] Miles L,Stephens,L.c,and Meyn,RE.Relation of apoptosis to cancer therapv.In Vivo.l994:8:665-666
[2] Nara A , Mizushima N , Yamamoto A , et al. SKD1 AAA AT-Pase-dependent endosomal transport is involved in autolysosomeformation. Cell Struct Funct , 2002, 27 : 29～37.
[3] Rez G;Palfia Z:Fellinger E.Occurrence and inhibition by cycloheximide of apoptosis in vincristine-treated murine pancreas. A role for autophagy[J] Acta-Biol-Hung,1991,42(l-3):133-140
[4] Khan MA.Effectsof myotoxins on skeletal muscle fibers[J].Prog-Neurobiol, 1995,46(5):541-560
[5] Bursch W, Hochegger K, Torok L, Marian B, Ellinger A, Hermann RS. (2000) Autophagic and apoptotic types of programmed cell death exhibit different fates of cytoskeletal filaments. J Cell Sci 113:1189-1198
[6] Tanida I,Ueno T, Kominami E. LC3 conjugation system in mammalian autophagy[ J ]. Int J Biochem Cell Biol, 2004,36 (12): 2503-2518.
[7] BurschW, Hochegger K, Torok L, et al. Autophagic and apoptotic types of programmed cell death exhibit different fates of cytoskeletal filaments[ J ]. J Cell Sci, 2000,113 (Pt 7): 1189-1198.
[8] Kanzawa T, Kondo Y, Ito H, et al. Induction of autophagic cell death in malignant glioma cells by arsenic trioxide[ J ]. Cancer Res, 2003,63 (9): 2103-2108.
[9] Chau YP, Lin SY, Chen JH, et al. Endostatin induces autophagic cell death in EAhy926 human endothelial cells [ J ]. Histol Histopathol, 2003,18(3) : 715-726.
[10] Haussinger G. The role of cellular hydration in the regulation of cell function[ J ]. Biochem J , 1996,313 (Pt 3) : 697-710.
[11] Kroemer G,Zamzami N,Susin SA.Mitochondrial control of apoptosis[J].lmmunol Today,1997,18:44-52
[12] Mcconkey DJ ,Orrenius S. The role of calcium in the regulation of apoptosis.Leukoc Biol ,1996 ;59 :775～782.
[13] Hamasaki M,Noda T, Ohsumi M,et al .Induction of autophagy and inhibition of tumorigenesis by Beclin 1 [J].Nature,1999,402(6762):672-676
[14] Meijer A J, Codogno P. Signalling and autophagy regulation in health, aging and disease [ J ]. Mol AspectsMed, 2006, 27 (526)
[15] Meijer A J, Codogno P. Signalling and autophagy regulation in health, aging and disease [ J ]. Mol AspectsMed, 2006,27 (526)
[16] Wen S,Stolarov J,Myers MP et al.PTEN controls humor-induced angiogenesis, Proc Natl Acad Sci USA,2001:98:4622-4627
[17] Petio t A , OgierDenis E, Blommaart EFC, et al. Distinct classes of phosphatidylinosito 13kinases are involved in signaling path ways that control macroautophagy in HT-29 cells. J Bio 1 Chem, 2000; 275 (2): 992-998
[18] Rognard J , Clark A S,N i Y, et al. PKB/protein kinase B is constitutively active in nonsmall cell lung cancer cells and promotes cellular survival and resistance to, chemo therapy and radiation [J ]. Cancer Res, 2001, 61(4) : 3986- 3997
[19] Citterio F , Pozzetto U , Romagnoli J , et al. Plasma levels of transforming growth factor P 1 in renal transplant recipients receiving different immunosuppressive regimens [ J ] . Transplant Proc ,2004 , 36 (3) : 698 - 699
[20] Ringel MD, Hayre N, Saito J, et all Overexp ression and overactivation of Akt in thyroid carcinoma [ J ]. Cancer Res, 2001, 61 (16) :6105 - 6111
[21] Perez Tenorio G, Stal O, Southeast Sweden Breast Cancer Group. Activation of Akt/PKB in breast cancer predicts a worse outcome among endocrine treated patients[ J ]1Br J Cancer, 2002, 86 (4): 540 - 545
[22] Ng G, Huang J. The Significance of autophagy in cancer[ J ]. Mol Carcinog, 2005,43 (4) : 183-187.
[23] Xue L , Fletcher GC , Tolkovsky AM. Autophagy is activated by apoptotic signaling in sympathetic neurons : an alternative mechanism of death execution. Mol Cell Neurosci, 1999 ,14 :180-198
[24] Bauvy C,Gane P,Arico S et al.Autophagy delays sulindacsulphide-induced apoptosis in the human intestinal colon cancer cell line HT-29.Exp Cell Res,2001;268:139-49
[25] Kanzawa T, Kondo Y.Ito H et al.Induction of autophagic cell death in malignant glioma cells by arsenic trioxide.CancerRes,2003;63:2103-2108.
[26] Saeki K, Yuo A, Okuma E et al. (2000) Bcl-2 down regulation causes autophagy in a caspase-independent mannar in human leukemic HL60 cells. Cell Death Differ 7:1263-1269.
[27] Shimizu S, Kanaseki T, Mizushima N et al. (2004) Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagic genes. Nat Cell Biol 6(12): 1221-1228
[28] Delshad A, Al-Tiraihi T. Ultra structure of apoptotic oligodendrocytes in the spinal cord of adult rat with longstanding axotomised sciaticnerve. Folia Neuropathology, 2001,39(3): 125-12825
[29] Folia Neuropathology, 2001,39(3): 125-12825
[30] Jellinger K A. Cell death mechanisms in neuron degeneration. Journal of Cellular and Molecular Medicine, 2001,5(1): 1—17
[31] Anglade P , Vyas S , Javoy Agid F , et al. Apoptosis and autophagy in nigral neurons of patients with Parkinson's disease . Histol Histopathology , 1997 , 12 :25～31.
[32] Kinch G, Hoffman K L, Rodrigues E M, et al. Steroid-triggered programmed cell death of amotoneuron is autophagic and involves structural changes in mitochondria. The Journal of Comparative Neurology, 2003,457(4): 384—403
[33] Kessel D, Reiners JJ, Hazeldine ST, et al. The role of autophagy in the death of L1210 leukemia cells initiated by the new antitumor agents, XK469 and SH80 [ J ]. Mol Cancer Ther, 2007, 6(1) :370-379.
[34] Camougrand N,Grelaud-Coq A, Marza E, et al. The product of the UTH1 gene, required for Bax-induced cell death in yeast, is involved in the response to rapamycin. Molecular Microbiology,2003,47(2): 495—50626
[35] Jellinger KA , Stadelmann C. Mechanisms of cell death in neurodegenerative disorders.J Neural Transm Suppl,2000a,59:95-114
[36]Shintani T and Klionsky DJ.(2004)Autophagy in health arid disease:a double-edged sword.Science(306):990-995
[37]Walker DH,Popov VL,Crocquet-valdes PA,Welsh CA,Feng HM.(1997)Cytokine-induced,nitric oxide-dependent,intracellular antirickettsial activity of mouse endothelial cells.Lab Invest 76:129-138.
[38]Talloczy Z Jiang W,Virgin HW 4th et al.(2002)Regulation of starvation and virus-induced autophagy by the eIF-alpha kinase signalling pathway.Proc Natl Acad Sci USA 99:190-195
[39]Webb JL,Ravikumar B,Atkins J,Skepper JN,Rubinsztein DC.(2003)Alpha-synuclein is degraded by both autophagy and the proteasome.J Biol Chem 278:25009-25013.
[40]Marino G and Lopez-Otin C.(2004)Autophagy:molecular mechanisms,physiological functions and relevance in human pathology.Cell Mol Life Sci 61(12):1439-1454.
[41]Gomez-Santos C,Ferrer I,Santidrian AF,Barrachina M,Gil J,Ambrosio S.(2003)Dopamine induces autophagic cell death and alpha-synuclein increase in human neuroblastoma SH-SY5Y cells.J Neurosci Res 73(3):341-350.
[42]Paludan C,Schmid D,LandthalerM,et al.EndogenousMHC class Ⅱ processing of a viral nuclear antigen after autophagy[J].Science,2005,307(5709):593-596.
[43]Lowe SW,Schmitt EM,Smith SW,et al.P53 is required for radiation-induced apoptosis in mouse thymocytes.Nature.1993;362:847
[44]Cohen LL.Apotosis.Immunol Today,1993;14:126
[45]Piao YJ,Ogawa Kazou.Ultrastructural and cytochemical observations on heterophagy and autophagy of macrophage in mouse thymus.Acta Histochem Cytochem,1985;18(6);615
[46]易静 汤雪明 自噬与类固醇激素调节的相互关系Acta Universitatis Medicinalis SecondaeShanghai Vol.14 No4 1994 313-317.
[47]Arico S,Petiot A,Bauvy C,et al.The tumor suppressor PTEN positively regulates macro autophagy by inhibiting the phosphatidylinosito 13kinase/protein kinase B pathway.Bio l Chem,2001;276(38):35243-35246
[48]Hanahan D,Weinberg RA.[J].Cell,2000,100(1):57-70.
[49]Mathew R,Kongara S,Beaudoin B,et al.Autophagy suppresses tumor progression by limiting chromosomal instability[J].Genes Dev,2007,21(11):1367-1381.
[50]Scott RC,Juhsz G,Neufeld TP.Direct induction of autophagy by Atg1 inhibits cell growth and induces apoptotic cell death[J].Curr Biol,2007,17(1):1211.
[51]Liang XH,Jackson S,Seaman M et al.(1999)Induction of autophagy and inhibition of tumorigenesis by Beclin 1.Nature 402:672-676.
[52]Cuervo AM.(2004)Autophagy:in sickness and in health.Trends Cell Biol 14(2):70-77.Review。
[53]Futreal PA,Liu Q,Shattuck Eidens D,et al.B RCA 1 mutations in primary breast and ovarian carcinomas.Science,1994;266(5182):120-122.
[54]Liang XH,Kleeman L K,Jiang HH,et al.Protection against fatal Sindbid virus encephalitis by Beclin 1,a novel Bcl-2 interacting protein.Viro 1,1998;72:8586-8596。
[55]Kihara A,Kabeya Y,Oh sumi Y,et al.Beclin 1 phosphatidylinosito 13k inase complex function at the trans Golgi network.EMBO,2001;2(4):330-335
[56]Scott R C,Schuldiner O,Neufeld T P.Neufeld.Role and regulation of starvation-induced autophagy in the drosophilafat body[J].Dev Cell,2004,7(2):167-178
[57]王赞宏,彭芝兰,段振玲,闫乃红 自噬基因Beclin 1 shRNA表达质粒的构建及其对宫颈癌细胞HeLa生长的作用J Sichuan Un iv(Med Sci Edi)2007;38(2):181 185
[58]Sherr CJ.Mammalian G1 cyclins.Cell,1993,73:1059.
[59]Gillett C,Fantl V,Bartek J,et al.Amp lification and over expression of cyclinD1 in breast cancer detected by immunohistochemical staining.Cancer Res,1994,54:1812
[60]Jain KK.Applications of biochip and microarray systems in pharmacogenomics[J].Pharmacogenomics,2000,1:289-307
[61]Cheng J,Moyer BD,Milewski M,et al.A Golgi-associated PDZ domain protein modulates cystic fibrosis transmembrane regulator plasma membrane expression.J Biol Chem,2002,227:3520-3529
[62]Futreal PA,L iu Q,Shattuck2Eidens D,et al.Beclin 1 mutations in primary breast and ovarian carcinomas.Science,1994;266(5182):120-122.
[63]Liang X H,Jackson S,Seaman M,et al.Induction of autophagy and inhibition of tumorigenesis by Beclin 1.Nature,1999,402(6 762):672-676
[64]Yue Z,J in S,Yang C,et al.Beclin 1,an autophagy gene essential for early embryonic development,is a haplo insufficient tumor suppressor.P roc Natl A cad Sci USA,2003;100(25):15077-15082
[65]上皮性卵巢癌中自噬基因Beclin 1的表达及其调控相关信号传导途径的研究J Sichuan Univ(Med Sci Edi)2007;38(2):239-242
[66]Yue Z,J in S,Yang C,et al.Beclin 1,an autophagy gene essential for early embryonic development,is a haplo insufficient tumor suppressor.Proc Natl Acad Sci USA,2003;100(25):15077-15082.
[67]Q u X,Yu J,Bhagat G,et al.Promotion of tumorigenesis by heterozygous disruption of the Beclin 1 autophagy gene.ClinInvest,2003;112(12):180-220
[68]Q u X,Yu J,Bhagat G,et al.Promotion of tumorigenesis by heterozygous disruption of the Beclin 1 autophagy gene.J Clin Invest,2003;112(12):1809-1820
[69]Scarlatti F,Bauvy C,VentrutiA,et al.Ceramidemediated macroautophagy involves inhibition of protein kinase B and upregulation of Beclin 1[J].J Biol Chem,2004,279(18):18384-18391
[70]QianW,Liu J,J in J,et al.Arsenic trioxide induces not only apoptosis but also autophagic cell death in leukemia cell lines via upregulation of Beclin 1[J].Leuk Res,2007,31(3):329-339
[71]Chia SJ,Tang WY,Elnatan J,et al.Prostate tumor from an Asian population examination of Bax.Bcl-2,P53 and ras and identification of Bax as a prognostic marker.Br J Cancer 2000;83(6):761
[72]Femando R I et al.Mol Biol Cell,2004,15(7):3266-3284
[73]Hawkins C J,Vaux D L.Analysis of the role of Bcl-2 in apoptosis.Iinmunol Rev,1994;141:127
[74]Tsujimoto Y,Corce CM.Analysis of the structure,transcripts and protein products Bcl-2,the gene involved in human follicular lymphoma.Proc Natl Acad Sci USA.1986;83:5214-5218
[75]Reed J C.Bcl-2 and the regulation of programmed cell death,J Cell Biol 1994:124:1
[76]Colombel M,Symmans F,Gil S,et al.Detection of the apoptosis-suppressing oncoprotein Bct-2 in hormone-refractory human prostate cancer,Am J Pathol 1993:143:390
[77]李家喜 王锦玲 郭志祥 刘振声 喉癌组织中抗凋亡基因Bcl-2蛋白的表达及临床相关性研究Med J Ch in PLA Vol 22 No 2 April 1997 110-112
[78]张教燕,张正民,韩仲明等调亡相关基因Bcl-2、BAX蛋白在喉鳞癌组织中的表达及其临床意义,耳鼻咽喉头颈外科 2001:8(1)27-30
[79]杨怀安,马杰,高坂知杰等抗调亡基因Bcl-2蛋白与放疗敏感的关系。中国医科大学学报。1998:27(1):54-56
[80]Gorski S M,Chittaranjan S,Pleasance ED,et al.A SAGE approach to discovery of genes involved in autophagic cell death.Curr Biol,2003,13:358-363
[81]Furuya D,Tsuji N,Yagihashi A,et al.Beclin 1 augmented cisdiarnmin edichloro platinum induced apoptosis via enhancing caspase29 activity.Experimental Cell Research,2005;307(1):26-40
[82]Chittenden T,Harrington E A.Introduction of apoptosis by Bcl-2 homologue BAK.Nature,1999;389:733-736
[83]Boya P,Gonzalez-Polo RA,Casares N et al.(2005)Inhibition of macroautophagy triggers apoptosis.Mol Cell Biol 25(3):1025-1040.
[84]Yanagisawa H,Miyashita T,Nakano Y,et al.Beclinl,a transmembrane protein interacting with Bcl-2/Bcl-xL,induces a caspase independent autophagic cell death. Cell Death Differ, 2003,10: 798-807
[85] Ng G, Huang J. The Significance of autophagy in cancer[ J ]. MolCarcinog, 2005, 43 (4): 183-187
[86] Pattingre S, Levine B. Bcl-2 inhibition of autophagy: a new route to cancer. Cancer Research, 2006; 66 (6): 2885-2888
[87] Liang XH, Jack son S, Seaman M , et al. Induction of autophagy and inhibition of tumorigenesis by Beclin 1. N ature, 1999; 402 (6762): 672-676
[88] Shintani T and Klionsky DJ. (2004) Autophagy in health and disease: a double-edged sword. Science (306):990-995
[89] Marino G and Lopez-Otin C. (2004) Autophagy: molecular mechanisms, physiological functions and relevance in human pathology. Cell Mol Life Sci 61(12):1439-1454.
[90] Cuervo A M. Autophagy: in sickness and in health[ J ]. Trends CellBiol, 2004, 14 (2): 70-77
[91] Paglin S, Hollister T, Delohery T et al. (2001) A novel response of cancer cells to radiation involves autophagy and formation of acidic vesicles. Cancer Res 61:439-444
[92] Alva AS, Gultekin SH, Baehrecke EH. (2004) Autophagy in human tumour cell survival or death? Cell Death Differ 11(9): 1046-1048
[93] Joyce JA ,Baruch A ,Chehade K,et al. [J ]. Cancer Cell ,2004,5 (5) :443-453.
[94] Chau YP, Lin SY, Chen JH et al. Endostatin induces autophagic cell death in EAhy926 human endothelial cells [ J ]Histol Histopathol, 2003, 18 (3) 715-726.
[95] Takeuchi H, Kondo Y,Fujiwara K, et al. Synergistic augmentation of rapamycin induced autophagy in malignant glioma cells by phosphatidylinosito-13 kinase / protein kinase B inhibitors [J]. Cancer Res, 2005, 65(8): 3336-3346.
[96] Kessel D, Reiners JJ, Hazeldine ST, et al. The role of autophagy in the death of L1210 leukemia cells initiated by the new antitumor agents, XK469 and SH80 [ J ]. Mol Cancer Ther, 2007, 6(1) :370-379.
[97] Herman AntosiewiczA, Johnson DE, Singh SV. Sulforaphane causes autophagy to inhibit release of cytochrome C and apoptosis in human prostate cancer cells [J].Cancer Res,2006,66(11):5828-5835.
[2] Arico S, Petiot A , Bauvy C, et al. The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinosito 13 kinase /protein kinase B pathway. Biol Chem, 2001; 276 (38): 35243-35246.
[3] Lock shin RA , Zakeri Z. Caspase-independent cell death. CurrOp in Cell Bio 1, 2002; 14 (6): 727-733
[4] Liang XH, Kleeman L K, Jiang HH, et al. Protection against fatal Sindbid virus encephalitis by Beclin 1, a novel Bcl-2 interacting protein. Viro 1, 1998; 72: 8586-8596.
[5] Kihara A , Kabeya Y, Ohsumi Y, et al. Beclin 1 phosphatidylinosito 13kinase complex function at the transgolginetwork. EMBO , 2001; 2 (4): 330-335.
[6] Liang XH, Jackson S, Seaman M , et al. Induction of autophagy and inhibition of tumorigenesis by Beclin 1. Nature, 1999; 402 (6762): 672-676
[7] Aita VM ,Liang XH,Murty W , et al. Cloning and genomic organization of Beclin 1, a candidate tumor suppressor gene on chromosome 17q21. Genomics, 1999; 59 (1): 59-65.
[8] Daisuke Furuya, Naoki Tsuji, Atsuhito Yagihashi, Naoki Watanabe. (2005) Beclinl augmented cis-diamminedichloroplatinum induced apoptosis via enhancing caspase-9 activity. Exp Cell Res 307: 26-40.
[9] Nara A , Mizushima N , Yamamoto A , et al. SKD1 AAA AT-Pase-dependent endosomal transport is involved in autolysosomeformation. Cell StructFunct, 2002, 27 : 29-37.
[10] Daniel J K. The molecular machinery of autophagy: unanswered questions. Journal of Cell Science,2005,118(1): 7—18.
[11] Petiot A , OgierDenis E, Blommaart EFC, et al. Distinct classes of phosphatidylinosito 13kinases are involved in signaling pathways that control macroautophagy in HT-29 cells.J Bio l Chem,2000;275(2):992-998.
[12]Klionsky DJ,Emr SD.Autophagy as a regulated pathway of cellular degradation.Science,2000,290:1717-1721.
[13]Futreal PA,Liu Q,Shattuck Eidens D,et al.Beclin 1 mutations in primary breast and ovarian carcinomas.Science,1994;266(5182):120-122.
[14]Liang XH,Kleeman L K,Jiang HH,et al.Protection against fatal Sindbid virus encephalitis by Beclin,a novelBcl-2 interacting protein.Viro l,1998;72:8586-8596.
[15]Meijer AJ and Codogno P.(2004)Regulation and role of autophagy in mammalian cells.Int J Biochem Cell Biol 36:2445-2462.
[16]Scott R C,Schuldiner O,Neufeld T P.Neufeld.Role and regulation of starvation-induced autophagy in the drosophilafat body[J].Dev Cell,2004,7(2):167-178.
[17]王赞宏,彭芝兰,段振玲,闰乃红自噬基因Beclin 1 shRNA表达质粒的构建及其对宫颈癌细胞HeLa生长的作用J Sichuan Univ(Med Sci Edi)2007;38(2):181 185
[18]Tassa A,Roux MP,Attaix D,et al.Class Ⅲphosphoinositide 3-kinase-Beclinl complex mediates the amino acid-dependent regulation of autophagy in C2C12myotubes Biochem J,2003,376:577-586
[19]Futreal PA,L iu Q,Shattuck Eidens D,et al.BRCA 1 mutations in primary breast and ovarian carcinomas.Science,1994;266(5182):120-122.
[20]Liang X H,Jackson S,Seaman M,et al.Induction of autophagy and inhibition of tumorigenesis by Beclin 1.Nature,1999,402(6762):672-676
[21]Yue Z,J in S,Yang C,et al.Beclin 1,an autophagy gene essential for early embryonic development,is a haplo insufficient tumor suppressor.Proc Natl Acad Sci USA,2003;100(25):15077-15082
[22]上皮性卵巢癌中自噬基因Beclin 1的表达及其调控相关信号传导途径的研究J Sichuan Un iv(Med Sc i Edi)2007;38(2):239 242
[23]Yue Z,J in S,Yang C,et al.Beclin 1,an autophagy gene essential for early embryonic development,is a haplo insufficient tumor suppressor.Proc Natl Acad Sci USA,2003;100(25):15077-15082.
[24]Qu X,Yu J,Bhagat G,et aI.Promotion of tumorigenesis by heterozygous disruption of the Beclin 1 autophagy gene.Clin Invest,2003;112(12):180-220
[25]Qu X,Yu J,Bhagat G,et al.Promotion of tumorigenesis by heterozygous disruption of the Beclin 1 autophagy gene.Clin Invest,2003;112(12):1800-1820
[26]Scarlatti F,Bauvy C,VentrutiA,et al.Ceramidemediated macroautophagy involves inhibition of protein kinase B and upregulation of Beclin 1[J].J Biol Chem,2004,279(18):18384-18391
[27]QianW,Liu J,J in J,et al.Arsenic trioxide induces not only apoptosis but also autophagic cell death in leukemia cell lines via upregulation of Beclin 1[J].Leuk Res,2007,31(3):329-339
[28]EI-DeryWS,Tokino Y,Velculescu VE,et al.WAF1,a potentialmediator of p53 tumor suppression[J].Cell,1993,75:817-825
[29]Rognard J,Clark A S,N i Y,et al.PKB/protein kinase B is constitutively active in nonsmall cell lung cancer cells and promotes cellular survival and resistance to,chemotherapy and radiation[J].Cancer Res,2001,61(4):3986-3997
[30]王赞宏,彭芝兰,段振玲,闫乃红 自噬基因Beclin 1 shRNA表达质粒的构建及其对宫颈癌细胞HeLa生长的作用J Sichuan Univ(Med Sci Edi)2007;38(2):181 185
[31]Chau YP,Lin SY,Chen JH et al.Endostatin induces autophagic cell death in EAhy926 human endothelial cells[J].Histol Histopathol,2003,18(3):715-726.
[32]Wen S,Stolarov J,Myers MP et al.PTEN controls humor-induced angiogenesis,Proc Natl Acad Sci USA,2001:98:4622-4627
[33]王赞宏,彭芝兰,段振玲,刘辉自噬基因B eclin 1在宫颈鳞癌中的蛋白表达及其临床意义],J Sichuan Univ(Med Sci Edi)2006;37(6):860 863
[34]Gomez-Santos C,Ferrer I,Santidrian A.F,Barrachina M,Gil J,Ambrosio S.(2003)Dopamine induces autophagic cell death and alpha-synuclein increase in human neuroblastoma SH-SY5Y cells.J Neurosci Res 73(3):341-350.
[35]Hoyer HansenM,Bastholm L,Mathiasen IS et al.Vitamin D analog EB1089triggers dramatic lysosomal changes and Beclin 1 mediated autophagic cell death [J].Cell Death Differ,2005,12(10):1297-309.
[36]Hawkins CJ,Vaux DL.Analysis of the role of Bcl-2 in apoptosis.Iinmunol Rev,1994;141:127
[37]Gorski SM,Chittaranjan S,Pleasance ED,et al.A SAGE approach to discovery of genes involved in autophagic cell death.Curr Biol,2003,13:358-363
[38]N g G,Huang J.The significance of autophagy in cancer.Molecular Carcinogenesis,2005;43(4):183-187
[39]Xue L,Fletcher GC,Tolkovsky AM.Autophagy is activated by apoptotic signaling in sympathetic neurons:an alternative mechanism of death execution.Mol Cell Neurosci,1999,14:180-198
[40]Chittenden T,Harrington EA.Introduction of apoptosis by Bcl-2 homologue BAK.Nature,1999;389:733-736
[41]Boya P,Gonzalez-Polo RA,Casares N et al.(2005)Inhibition of macroautophagy triggers apoptosis.Mol Cell Biol 25(3):1025-1040.
[42]Yanagisawa H,Miyashita T,Nakano Y,et al.Beclin 1,a transmembrane protein interacting with Bcl-2/Bcl-xL,induces a caspase independent autophagic cell death.Cell Death Differ,2003,10:798-807
[43]Ng G,Huang J.The Significance of autophagy in cancer[J].MolCarcinog,2005,43(4):183-187
[44]Pattingre S,L evine B.Bcl-2 inhibition of autophagy:a new route to cancer.Cancer Research,2006;66(6):2885-2888
[45]Liang XH,Jack son S,Seaman M,et al.Induction of autophagy and inhibition of tumorigenesis by Beclin 1.Nature,1999;402(6762):672-676
[46]李家喜,王锦玲,郭志祥,刘振声喉癌组织中抗凋亡基因Bcl-2蛋白的表达及临床相关性研究Med J Ch in PLA Vol 22 No 2 April 1997 110-112
[47]张敏燕,张正民,韩仲明等调亡相关基因Bcl-2、BAX蛋白在喉鳞癌组织中的表达及其临床意义,耳鼻咽喉头颈外科 2001;8(1)27-30
[48]Shintani T and Klionsky DJ.(2004)Autophagy in health and disease:a double-edged sword. Science (306):990-995
[49] Marino G and Lopez-Otin C. (2004) Autophagy: molecular mechanisms, physiological functions and relevance in human pathology. Cell Mol Life Sci 61(12):1439-1454.
[50] Alva AS, Gultekin SH, Baehrecke EH. (2004) Autophagy in human tumour cell survival or death? Cell Death Differ 11(9): 1046-1048
[51] Paglin S, Hollister T, Delohery T et al. (2001) A novel response of cancer cells to radiation involves autophagy and formation of acidic vesicles. Cancer Res 61:439-444
[52] Joyce JA ,Baruch A ,Chehade K,et al. [J ]. Cancer Cell ,2004,5 (5) :443-453. Florez-McClure ML, Linseman DA, Heidenreich KA et al. (2004) The p75 neurotrophin receptor can induce autophagy and death of cerebellar Purkinje neurons. J Neurosci 24(19): 4498-4509
[53] Bauvy C,Gane P,Arico S et al.Autophagy delays sulindac sulphide-induced apoptosis in the human intestinal colon cancer cell line HT-29.Exp Cell Res,2001;268:139-49
[54] Florez-McClure ML, Linseman DA, Heidenreich KA et al. (2004) The p75 neurotrophin receptor can induce autophagy and death of cerebellar Purkinje neurons. J Neurosci 24(19): 4498-4509
[1] Miles L,Stephens,L.c,and Meyn,RE.Relation of apoptosis to cancer therapv.In Vivo.l994:8:665-666
[2] Nara A , Mizushima N , Yamamoto A , et al. SKD1 AAA AT-Pase-dependent endosomal transport is involved in autolysosomeformation. Cell Struct Funct , 2002, 27 : 29～37.
[3] Rez G;Palfia Z:Fellinger E.Occurrence and inhibition by cycloheximide of apoptosis in vincristine-treated murine pancreas. A role for autophagy[J] Acta-Biol-Hung,1991,42(l-3):133-140
[4] Khan MA.Effectsof myotoxins on skeletal muscle fibers[J].Prog-Neurobiol, 1995,46(5):541-560
[5] Bursch W, Hochegger K, Torok L, Marian B, Ellinger A, Hermann RS. (2000) Autophagic and apoptotic types of programmed cell death exhibit different fates of cytoskeletal filaments. J Cell Sci 113:1189-1198
[6] Tanida I,Ueno T, Kominami E. LC3 conjugation system in mammalian autophagy[ J ]. Int J Biochem Cell Biol, 2004,36 (12): 2503-2518.
[7] BurschW, Hochegger K, Torok L, et al. Autophagic and apoptotic types of programmed cell death exhibit different fates of cytoskeletal filaments[ J ]. J Cell Sci, 2000,113 (Pt 7): 1189-1198.
[8] Kanzawa T, Kondo Y, Ito H, et al. Induction of autophagic cell death in malignant glioma cells by arsenic trioxide[ J ]. Cancer Res, 2003,63 (9): 2103-2108.
[9] Chau YP, Lin SY, Chen JH, et al. Endostatin induces autophagic cell death in EAhy926 human endothelial cells [ J ]. Histol Histopathol, 2003,18(3) : 715-726.
[10] Haussinger G. The role of cellular hydration in the regulation of cell function[ J ]. Biochem J , 1996,313 (Pt 3) : 697-710.
[11] Kroemer G,Zamzami N,Susin SA.Mitochondrial control of apoptosis[J].lmmunol Today,1997,18:44-52
[12] Mcconkey DJ ,Orrenius S. The role of calcium in the regulation of apoptosis.Leukoc Biol ,1996 ;59 :775～782.
[13] Hamasaki M,Noda T, Ohsumi M,et al .Induction of autophagy and inhibition of tumorigenesis by Beclin 1 [J].Nature,1999,402(6762):672-676
[14] Meijer A J, Codogno P. Signalling and autophagy regulation in health, aging and disease [ J ]. Mol AspectsMed, 2006, 27 (526)
[15] Meijer A J, Codogno P. Signalling and autophagy regulation in health, aging and disease [ J ]. Mol AspectsMed, 2006,27 (526)
[16] Wen S,Stolarov J,Myers MP et al.PTEN controls humor-induced angiogenesis, Proc Natl Acad Sci USA,2001:98:4622-4627
[17] Petio t A , OgierDenis E, Blommaart EFC, et al. Distinct classes of phosphatidylinosito 13kinases are involved in signaling path ways that control macroautophagy in HT-29 cells. J Bio 1 Chem, 2000; 275 (2): 992-998
[18] Rognard J , Clark A S,N i Y, et al. PKB/protein kinase B is constitutively active in nonsmall cell lung cancer cells and promotes cellular survival and resistance to, chemo therapy and radiation [J ]. Cancer Res, 2001, 61(4) : 3986- 3997
[19] Citterio F , Pozzetto U , Romagnoli J , et al. Plasma levels of transforming growth factor P 1 in renal transplant recipients receiving different immunosuppressive regimens [ J ] . Transplant Proc ,2004 , 36 (3) : 698 - 699
[20] Ringel MD, Hayre N, Saito J, et all Overexp ression and overactivation of Akt in thyroid carcinoma [ J ]. Cancer Res, 2001, 61 (16) :6105 - 6111
[21] Perez Tenorio G, Stal O, Southeast Sweden Breast Cancer Group. Activation of Akt/PKB in breast cancer predicts a worse outcome among endocrine treated patients[ J ]1Br J Cancer, 2002, 86 (4): 540 - 545
[22] Ng G, Huang J. The Significance of autophagy in cancer[ J ]. Mol Carcinog, 2005,43 (4) : 183-187.
[23] Xue L , Fletcher GC , Tolkovsky AM. Autophagy is activated by apoptotic signaling in sympathetic neurons : an alternative mechanism of death execution. Mol Cell Neurosci, 1999 ,14 :180-198
[24] Bauvy C,Gane P,Arico S et al.Autophagy delays sulindacsulphide-induced apoptosis in the human intestinal colon cancer cell line HT-29.Exp Cell Res,2001;268:139-49
[25] Kanzawa T, Kondo Y.Ito H et al.Induction of autophagic cell death in malignant glioma cells by arsenic trioxide.CancerRes,2003;63:2103-2108.
[26] Saeki K, Yuo A, Okuma E et al. (2000) Bcl-2 down regulation causes autophagy in a caspase-independent mannar in human leukemic HL60 cells. Cell Death Differ 7:1263-1269.
[27] Shimizu S, Kanaseki T, Mizushima N et al. (2004) Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagic genes. Nat Cell Biol 6(12): 1221-1228
[28] Delshad A, Al-Tiraihi T. Ultra structure of apoptotic oligodendrocytes in the spinal cord of adult rat with longstanding axotomised sciaticnerve. Folia Neuropathology, 2001,39(3): 125-12825
[29] Folia Neuropathology, 2001,39(3): 125-12825
[30] Jellinger K A. Cell death mechanisms in neuron degeneration. Journal of Cellular and Molecular Medicine, 2001,5(1): 1—17
[31] Anglade P , Vyas S , Javoy Agid F , et al. Apoptosis and autophagy in nigral neurons of patients with Parkinson's disease . Histol Histopathology , 1997 , 12 :25～31.
[32] Kinch G, Hoffman K L, Rodrigues E M, et al. Steroid-triggered programmed cell death of amotoneuron is autophagic and involves structural changes in mitochondria. The Journal of Comparative Neurology, 2003,457(4): 384—403
[33] Kessel D, Reiners JJ, Hazeldine ST, et al. The role of autophagy in the death of L1210 leukemia cells initiated by the new antitumor agents, XK469 and SH80 [ J ]. Mol Cancer Ther, 2007, 6(1) :370-379.
[34] Camougrand N,Grelaud-Coq A, Marza E, et al. The product of the UTH1 gene, required for Bax-induced cell death in yeast, is involved in the response to rapamycin. Molecular Microbiology,2003,47(2): 495—50626
[35] Jellinger KA , Stadelmann C. Mechanisms of cell death in neurodegenerative disorders.J Neural Transm Suppl,2000a,59:95-114
[36]Shintani T and Klionsky DJ.(2004)Autophagy in health arid disease:a double-edged sword.Science(306):990-995
[37]Walker DH,Popov VL,Crocquet-valdes PA,Welsh CA,Feng HM.(1997)Cytokine-induced,nitric oxide-dependent,intracellular antirickettsial activity of mouse endothelial cells.Lab Invest 76:129-138.
[38]Talloczy Z Jiang W,Virgin HW 4th et al.(2002)Regulation of starvation and virus-induced autophagy by the eIF-alpha kinase signalling pathway.Proc Natl Acad Sci USA 99:190-195
[39]Webb JL,Ravikumar B,Atkins J,Skepper JN,Rubinsztein DC.(2003)Alpha-synuclein is degraded by both autophagy and the proteasome.J Biol Chem 278:25009-25013.
[40]Marino G and Lopez-Otin C.(2004)Autophagy:molecular mechanisms,physiological functions and relevance in human pathology.Cell Mol Life Sci 61(12):1439-1454.
[41]Gomez-Santos C,Ferrer I,Santidrian AF,Barrachina M,Gil J,Ambrosio S.(2003)Dopamine induces autophagic cell death and alpha-synuclein increase in human neuroblastoma SH-SY5Y cells.J Neurosci Res 73(3):341-350.
[42]Paludan C,Schmid D,LandthalerM,et al.EndogenousMHC class Ⅱ processing of a viral nuclear antigen after autophagy[J].Science,2005,307(5709):593-596.
[43]Lowe SW,Schmitt EM,Smith SW,et al.P53 is required for radiation-induced apoptosis in mouse thymocytes.Nature.1993;362:847
[44]Cohen LL.Apotosis.Immunol Today,1993;14:126
[45]Piao YJ,Ogawa Kazou.Ultrastructural and cytochemical observations on heterophagy and autophagy of macrophage in mouse thymus.Acta Histochem Cytochem,1985;18(6);615
[46]易静 汤雪明 自噬与类固醇激素调节的相互关系Acta Universitatis Medicinalis SecondaeShanghai Vol.14 No4 1994 313-317.
[47]Arico S,Petiot A,Bauvy C,et al.The tumor suppressor PTEN positively regulates macro autophagy by inhibiting the phosphatidylinosito 13kinase/protein kinase B pathway.Bio l Chem,2001;276(38):35243-35246
[48]Hanahan D,Weinberg RA.[J].Cell,2000,100(1):57-70.
[49]Mathew R,Kongara S,Beaudoin B,et al.Autophagy suppresses tumor progression by limiting chromosomal instability[J].Genes Dev,2007,21(11):1367-1381.
[50]Scott RC,Juhsz G,Neufeld TP.Direct induction of autophagy by Atg1 inhibits cell growth and induces apoptotic cell death[J].Curr Biol,2007,17(1):1211.
[51]Liang XH,Jackson S,Seaman M et al.(1999)Induction of autophagy and inhibition of tumorigenesis by Beclin 1.Nature 402:672-676.
[52]Cuervo AM.(2004)Autophagy:in sickness and in health.Trends Cell Biol 14(2):70-77.Review。
[53]Futreal PA,Liu Q,Shattuck Eidens D,et al.B RCA 1 mutations in primary breast and ovarian carcinomas.Science,1994;266(5182):120-122.
[54]Liang XH,Kleeman L K,Jiang HH,et al.Protection against fatal Sindbid virus encephalitis by Beclin 1,a novel Bcl-2 interacting protein.Viro 1,1998;72:8586-8596。
[55]Kihara A,Kabeya Y,Oh sumi Y,et al.Beclin 1 phosphatidylinosito 13k inase complex function at the trans Golgi network.EMBO,2001;2(4):330-335
[56]Scott R C,Schuldiner O,Neufeld T P.Neufeld.Role and regulation of starvation-induced autophagy in the drosophilafat body[J].Dev Cell,2004,7(2):167-178
[57]王赞宏,彭芝兰,段振玲,闫乃红 自噬基因Beclin 1 shRNA表达质粒的构建及其对宫颈癌细胞HeLa生长的作用J Sichuan Un iv(Med Sci Edi)2007;38(2):181 185
[58]Sherr CJ.Mammalian G1 cyclins.Cell,1993,73:1059.
[59]Gillett C,Fantl V,Bartek J,et al.Amp lification and over expression of cyclinD1 in breast cancer detected by immunohistochemical staining.Cancer Res,1994,54:1812
[60]Jain KK.Applications of biochip and microarray systems in pharmacogenomics[J].Pharmacogenomics,2000,1:289-307
[61]Cheng J,Moyer BD,Milewski M,et al.A Golgi-associated PDZ domain protein modulates cystic fibrosis transmembrane regulator plasma membrane expression.J Biol Chem,2002,227:3520-3529
[62]Futreal PA,L iu Q,Shattuck2Eidens D,et al.Beclin 1 mutations in primary breast and ovarian carcinomas.Science,1994;266(5182):120-122.
[63]Liang X H,Jackson S,Seaman M,et al.Induction of autophagy and inhibition of tumorigenesis by Beclin 1.Nature,1999,402(6 762):672-676
[64]Yue Z,J in S,Yang C,et al.Beclin 1,an autophagy gene essential for early embryonic development,is a haplo insufficient tumor suppressor.P roc Natl A cad Sci USA,2003;100(25):15077-15082
[65]上皮性卵巢癌中自噬基因Beclin 1的表达及其调控相关信号传导途径的研究J Sichuan Univ(Med Sci Edi)2007;38(2):239-242
[66]Yue Z,J in S,Yang C,et al.Beclin 1,an autophagy gene essential for early embryonic development,is a haplo insufficient tumor suppressor.Proc Natl Acad Sci USA,2003;100(25):15077-15082.
[67]Q u X,Yu J,Bhagat G,et al.Promotion of tumorigenesis by heterozygous disruption of the Beclin 1 autophagy gene.ClinInvest,2003;112(12):180-220
[68]Q u X,Yu J,Bhagat G,et al.Promotion of tumorigenesis by heterozygous disruption of the Beclin 1 autophagy gene.J Clin Invest,2003;112(12):1809-1820
[69]Scarlatti F,Bauvy C,VentrutiA,et al.Ceramidemediated macroautophagy involves inhibition of protein kinase B and upregulation of Beclin 1[J].J Biol Chem,2004,279(18):18384-18391
[70]QianW,Liu J,J in J,et al.Arsenic trioxide induces not only apoptosis but also autophagic cell death in leukemia cell lines via upregulation of Beclin 1[J].Leuk Res,2007,31(3):329-339
[71]Chia SJ,Tang WY,Elnatan J,et al.Prostate tumor from an Asian population examination of Bax.Bcl-2,P53 and ras and identification of Bax as a prognostic marker.Br J Cancer 2000;83(6):761
[72]Femando R I et al.Mol Biol Cell,2004,15(7):3266-3284
[73]Hawkins C J,Vaux D L.Analysis of the role of Bcl-2 in apoptosis.Iinmunol Rev,1994;141:127
[74]Tsujimoto Y,Corce CM.Analysis of the structure,transcripts and protein products Bcl-2,the gene involved in human follicular lymphoma.Proc Natl Acad Sci USA.1986;83:5214-5218
[75]Reed J C.Bcl-2 and the regulation of programmed cell death,J Cell Biol 1994:124:1
[76]Colombel M,Symmans F,Gil S,et al.Detection of the apoptosis-suppressing oncoprotein Bct-2 in hormone-refractory human prostate cancer,Am J Pathol 1993:143:390
[77]李家喜 王锦玲 郭志祥 刘振声 喉癌组织中抗凋亡基因Bcl-2蛋白的表达及临床相关性研究Med J Ch in PLA Vol 22 No 2 April 1997 110-112
[78]张教燕,张正民,韩仲明等调亡相关基因Bcl-2、BAX蛋白在喉鳞癌组织中的表达及其临床意义,耳鼻咽喉头颈外科 2001:8(1)27-30
[79]杨怀安,马杰,高坂知杰等抗调亡基因Bcl-2蛋白与放疗敏感的关系。中国医科大学学报。1998:27(1):54-56
[80]Gorski S M,Chittaranjan S,Pleasance ED,et al.A SAGE approach to discovery of genes involved in autophagic cell death.Curr Biol,2003,13:358-363
[81]Furuya D,Tsuji N,Yagihashi A,et al.Beclin 1 augmented cisdiarnmin edichloro platinum induced apoptosis via enhancing caspase29 activity.Experimental Cell Research,2005;307(1):26-40
[82]Chittenden T,Harrington E A.Introduction of apoptosis by Bcl-2 homologue BAK.Nature,1999;389:733-736
[83]Boya P,Gonzalez-Polo RA,Casares N et al.(2005)Inhibition of macroautophagy triggers apoptosis.Mol Cell Biol 25(3):1025-1040.
[84]Yanagisawa H,Miyashita T,Nakano Y,et al.Beclinl,a transmembrane protein interacting with Bcl-2/Bcl-xL,induces a caspase independent autophagic cell death. Cell Death Differ, 2003,10: 798-807
[85] Ng G, Huang J. The Significance of autophagy in cancer[ J ]. MolCarcinog, 2005, 43 (4): 183-187
[86] Pattingre S, Levine B. Bcl-2 inhibition of autophagy: a new route to cancer. Cancer Research, 2006; 66 (6): 2885-2888
[87] Liang XH, Jack son S, Seaman M , et al. Induction of autophagy and inhibition of tumorigenesis by Beclin 1. N ature, 1999; 402 (6762): 672-676
[88] Shintani T and Klionsky DJ. (2004) Autophagy in health and disease: a double-edged sword. Science (306):990-995
[89] Marino G and Lopez-Otin C. (2004) Autophagy: molecular mechanisms, physiological functions and relevance in human pathology. Cell Mol Life Sci 61(12):1439-1454.
[90] Cuervo A M. Autophagy: in sickness and in health[ J ]. Trends CellBiol, 2004, 14 (2): 70-77
[91] Paglin S, Hollister T, Delohery T et al. (2001) A novel response of cancer cells to radiation involves autophagy and formation of acidic vesicles. Cancer Res 61:439-444
[92] Alva AS, Gultekin SH, Baehrecke EH. (2004) Autophagy in human tumour cell survival or death? Cell Death Differ 11(9): 1046-1048
[93] Joyce JA ,Baruch A ,Chehade K,et al. [J ]. Cancer Cell ,2004,5 (5) :443-453.
[94] Chau YP, Lin SY, Chen JH et al. Endostatin induces autophagic cell death in EAhy926 human endothelial cells [ J ]Histol Histopathol, 2003, 18 (3) 715-726.
[95] Takeuchi H, Kondo Y,Fujiwara K, et al. Synergistic augmentation of rapamycin induced autophagy in malignant glioma cells by phosphatidylinosito-13 kinase / protein kinase B inhibitors [J]. Cancer Res, 2005, 65(8): 3336-3346.
[96] Kessel D, Reiners JJ, Hazeldine ST, et al. The role of autophagy in the death of L1210 leukemia cells initiated by the new antitumor agents, XK469 and SH80 [ J ]. Mol Cancer Ther, 2007, 6(1) :370-379.
[97] Herman AntosiewiczA, Johnson DE, Singh SV. Sulforaphane causes autophagy to inhibit release of cytochrome C and apoptosis in human prostate cancer cells [J].Cancer Res,2006,66(11):5828-5835.