两个维甲酸特异激活表达的促分化基因的结构和功能鉴定
摘要
目前认为，恶性肿瘤是一类因多个基因改变而影响细胞正常生长和分化调节的疾病。以该理论为基础的肿瘤分化治疗，目的不是单纯地杀死肿瘤细胞，而是要让那些具有分化潜能的肿瘤细胞向成熟的分化表型发展。在过去的十年中，本实验室一直在探索一条分离肿瘤促分化基因的新途径，即用分化诱导剂—全反式维甲酸诱导某些肿瘤细胞系分化，再利用cDNA文库的递减杂交策略分离出那些在分化过程中特异表达的基因，并进一步研究它们作为治疗肿瘤的目的基因的可能性。至今，已经从食管癌细胞中得到一个具有很强的肿瘤抑制功效的新基因：RATS1基因。
在上述理论及实践的指导下，本室黎伯铨等运用相同的策略，建立了维甲酸诱导前后的肺腺癌细胞系GLC-82的cDNA文库，经6轮递减杂交及初步筛选，得到124个维甲酸激活的cDNA克隆。本研究的目的即是从这些cDNA克隆中筛选出那些真正为维甲酸特异激活表达的、具有促分化功能的新基因，探讨它们与肺癌发生、发展的关系，深化维甲酸的作用机理，为克隆出这些基因以至用于肺癌的基因治疗提供基础。
本文运用限制酶切分析cDNA文库的Southern杂交，
It's known that the multistep carcinogenic process is often characterized by loss of normal control over proliferation and aberrant patterns of difFerentiation. The principle of tumor differentiation therapy has been developed on the basis of these facts. It doesn't attempt to kill tumor cells, but focuses on the suppression of cell proliferation and the induction of terminal differentiation. During the last decade, our lab has been developing a novel strategy for isolating differentiation-inducing genes from human cancers: terminal differentiation of human cancer cell lines is induced by all-trans-retinoic acid(RA), then repeated subtraction hybridization between cDNA libraries constructed from cells before and after RA-treatrnent is used' to isolate genes specifically activated by RA. The biological effects of these genes on parental cells are then tested in vitro. So far, a novel gene—RATS1 has been isolated from esophageal cancer cell line which possesses strong proliferation-suppressing and differentiation-inducing effect.
With similar strategy, our lab also attempted to isolate those differentiation-inducing genes from lung cancer cells: three cDNA libraries were constructed, one was from human lung adenocarcinoma cell line GLC-82, named Lib.GLC-82; the other were from GLC-82 cells treated with RA for 1 and 4 days, named Lib.GLC-82.RAl and Lib.GLC-82.RA4. After the 6th round of subtraction hybridization, 124 differential cDNA clones were obtained. This study is concerned on identifying those novel genes, investigating their correlation with carcinogenesis of lung cancer, dissecting the mechanism of RA's action, and evaluate their biological functions in their parental cells GLC-82.
在上述理论及实践的指导下，本室黎伯铨等运用相同的策略，建立了维甲酸诱导前后的肺腺癌细胞系GLC-82的cDNA文库，经6轮递减杂交及初步筛选，得到124个维甲酸激活的cDNA克隆。本研究的目的即是从这些cDNA克隆中筛选出那些真正为维甲酸特异激活表达的、具有促分化功能的新基因，探讨它们与肺癌发生、发展的关系，深化维甲酸的作用机理，为克隆出这些基因以至用于肺癌的基因治疗提供基础。
本文运用限制酶切分析cDNA文库的Southern杂交，
It's known that the multistep carcinogenic process is often characterized by loss of normal control over proliferation and aberrant patterns of difFerentiation. The principle of tumor differentiation therapy has been developed on the basis of these facts. It doesn't attempt to kill tumor cells, but focuses on the suppression of cell proliferation and the induction of terminal differentiation. During the last decade, our lab has been developing a novel strategy for isolating differentiation-inducing genes from human cancers: terminal differentiation of human cancer cell lines is induced by all-trans-retinoic acid(RA), then repeated subtraction hybridization between cDNA libraries constructed from cells before and after RA-treatrnent is used' to isolate genes specifically activated by RA. The biological effects of these genes on parental cells are then tested in vitro. So far, a novel gene—RATS1 has been isolated from esophageal cancer cell line which possesses strong proliferation-suppressing and differentiation-inducing effect.
With similar strategy, our lab also attempted to isolate those differentiation-inducing genes from lung cancer cells: three cDNA libraries were constructed, one was from human lung adenocarcinoma cell line GLC-82, named Lib.GLC-82; the other were from GLC-82 cells treated with RA for 1 and 4 days, named Lib.GLC-82.RAl and Lib.GLC-82.RA4. After the 6th round of subtraction hybridization, 124 differential cDNA clones were obtained. This study is concerned on identifying those novel genes, investigating their correlation with carcinogenesis of lung cancer, dissecting the mechanism of RA's action, and evaluate their biological functions in their parental cells GLC-82.
引文
1. Fisher PB and Rowley PT. Status of differentiation therapy of cancer. Waxman S, Rossi GB and Takaku F(eds). Raven Press, Inc.: New York, pp201-213.
2. Knndson AG. Antioncogeues and human cancer. Proc Natl Acad Sci USA 9: 10914-10921, 1993
3. Weiberg RA. The integration of molecular genetics into cancer management. Cancer 70: 1653-1658, 1992
4．赵晓航，王秀琴，彭仁玲，闰水忠，吴旻 c-myc反义RNA特异性诱发人食管癌细胞程序性死亡 中国科学B辑 23卷，11期：1185-1192，1993
5. Zhang W-W. Fang. XM, Mazur W, et al. Hingh-efficiency gene transfer and high-level expression of wild-type p53 in human lung cancer cells mediated by recombinant adenovirus, Gene cancer therapy. 1(1): 5-13, 1994
6. Fujiwara T, Grimm D, Mukhopadhyay T, et al. Induction of chemosensitivity in human lung cancer in vivo by adenovirus-mediated transfer of the wild-type p53 gene. Cancer Res. 54: 2287-2291, 1994
7. Sachs L. Control of normal cell differentiation and the phenotypic reversion of malignancy in myeloid leukaemia Nature 274: 535-539, 1978
8．冯骆，王秀琴，吴旻等，从人食管癌细胞系分离分化基因的新方法 中国科学(B辑)，20：1059-1066，1991
9．杨晓光，丁芳，郑文岭，王秀琴，吴旻 cDNA从538的表达诱导亲本恶性细胞系发生终末分化和凋亡．中国医学科学院学报16卷，4期：251-253，1994
10．杨晓光，任力强，丁芳，郑文岭，王秀琴，周传农，吴旻 cDNA RA538对三种人癌细胞系抑制作用的研究，中国医学科学院学报 16卷，第4期：254
11．黎伯铨，维甲酸诱导的人肺腺癌细胞促分化基因的克隆，第三军医大学，博士论文，1995年5月
12．金冬雁，黎孟枫等译 分子克隆实验指南，萨姆布鲁克，弗里奇，曼尼阿蒂斯著 科学出版社，1992
13. Chomezynski P and Sacchi N. Single-step method of RNA isolation by acid guanidium thicocyanate-phenol-chloroform extraction. Anal Biochem. l62: 156-159, 198714．卢圣栋主编，现代分子生物学实验技术，高等教育出版社，1993，pp109
15．林万明主编 核酸探针杂交实验技术，中国科学技术出版社 1991年，北京
16．雷薇，吴旻 维甲酸对细胞增殖分化调节的分子机制，国外医学分子生物学分册16(2)：83-86，1994
17. Mulligan RC and Beig P. Selection for animal cells that express the Escherichia coli gene coding for xanthine-guanine phosphoribosyl transferase. Proc, Natl, Acad. Sci. USA. 78(4): 2072-2076, 1981
18. Chapman AB, Costello MA, Riugold GM et al. Amplification and hormone-regulated expression of a monse mammary tumor virus-Eco gpt fusion plasmid in mouse 3T6 cells. Mol. Cell. Biol. 3(8): 1421-1429, 1983
19. Klessing DF, Brough DE and Cleghon V. Introduction, stable integration and controlled expression of a chimeric adenovirus gene whose product is toxic to the recipient human cell. Mol. Celi. Biol. 4(7): 1354-1362, 1984
20. Schraml P, Shipman R, Colobi M, et al. Identification of genes differentially expressed in normal lung nod non-small cell lung carcinoma tissue. Cancer Res. 54: 5236-5240, 1994
21. Steinnan RA, Hoffman B, Ira A et al, Iaduction of p21 (WAF-1/CIP1)during differentiation. Oncogene. 9: 3389-3396, 1994
22. Jiang HP, Lin J, Su Z et al. Induction of differentiation in human promyelocytic RL-60 leukemia cells activates p21, WAF1/CIP1. Oncogene. 9: 3397-3406, 1994
23. Matin SJ, Green DR and Cotter TG. Dicing with death: dissecting the components of the apoptosis mechinery. TIBS. 19: 26-30, 1994
24. Williams GT et al. Prosrammed cell death: apoptosis and oacogeuesis. Cell, 65: 1097, 1991
25. Eastman A. Activation of programmed cell death by anticancer agents: cisplatin as a model system. Cancer Cells. 2: 275-280, 1990
26. Furuya Y and Isaacs JT. Proliferation-indepen-dent programmed cell death as a therapeutic target for prostate cancer. The Cancer Bulletin. 46(2): 173-179, 1994
27. Wyllie AH. Apoptosis(The 1992 Frank Rose Memorial Lecture). Br. J. Cuncer. 67: 205-208, 199328. Kosa K, Megers K, and Deluca LM. Transformation of NIH3T3 cells with ras oncogenes abrogated the retinoic acid induction of tissue transglutaminase. Biochem. Biophys. Res. Comm. 196(3): 1025-1033, 1993
29．黎伯铨，雷薇，张雪燕，王秀琴，毛宝龄，吴旻 维甲酸激活的人肺腺癌细胞促分化基因的克隆和鉴定。中国首届人类基因诊断，治疗与预防研讨会论文集，pp17，1994，北京
30. Foo- Min Liew and Kiyofuni Yamanishi. Regulation of transglntaminase I gene expression by 12- 0-tetradecanoylphorbol-13-acetate, dexame- thasone and retinoic acid in cultured human kers- tinocytes. Exp. Cell Res. 202: 310-315, 1992
31. Nervi C, Voliberg TM, Chambon P and Jetten AM. Expression of nuclear retinoic acid receptors in normal tracheobronchial cells and in lung carcinoma cells. Exp. Cell Res. 195: 165-170, 1991
32. Kalemlerian GP, Jasti RK, Celano P, et al. All-trans -retinoic acid alters aye gene expression and inhibits in vitro progression in small cell lung cancer. Cell Growth & Differentiation 5: 55-60, 1994
33. Eguchi Y, Itoh T and Tomizawa J-I. Antisense RNA. Annu. Rev Biochem. 60: 631-652, 1991
34. Okubo K, Hori N, Matsubara K et al. Large scale cDNA sequencing for analysis of quantita- tire and qualitative aspects of gene expression. Nature Genetics. 2: 173-179, 1992
35. Adams MD, Kerlavage AR, Veter JC et al. 3400 new expressed sequence tags identify diversity of transcripts in human brain. Nuture Genetics. 4: 256-267, 1993
36. Dusrmmond TC. The nomenclature of the so- called accessory food factor(vitamins). Biochem J. 14: 660, 1920
37. Wolbach, S. B., and Howe, P. R., Tissue chdanges following deprivation of fat soluble A vitamin. J. Exp. Med., 42: 753-777, 1925
38. ChytilF: Retinoic acid: Biochemistry and metabolism. J. Am Acad Dermatol 15: 741-747, 1986
39. Cope F. and Wills J. Retinoid receptor antisense DNAs inhibit alkaline phosphatase induction and clonogenicity in malisnant keratinocytes. Proc. Nutl kcad Sci USA 86: 5590-5594, 198940. Napoli J., Pramanik B. Willams J. et al. Quantification of retinoicd acid by gas-liquid chromatography-mass spectometry total versus all-trans-retinoic acid in human plasma. J. Lipid Res. 26: 387-392, 1985
41. Thaller C. and Eichele G. Identification and spatial distribution of retinoids in the developing chick limb bud. Nature. 327: 625-628, 1987
42. Tickle C. Retinoic acid and chick limb bud development. Development. 1: 113-121, 1991(suppl)
43. Durston A, Timmermans J. and Hare W. el al. Retinoic acid causes an anteroposterior transformation in the developing central nervous system. Nature 340: 140-144, 1989
44. Amatruda T. and Keoffler H. Retinoids and cells of the hematopoietic system, in Sherman M. (ed): Retinoids and cell differentiation. Boca Raton, FL, CRC Press, 1986, pp: 79-103
45. Doner D and Keoffler H. Retinoie acid enhances colony-stimulating factor- induced elonal growth of normal human myeloid progenitor cells in vitro. Exp. Cell Res. 138: 193-198, 1982
46. Ozato Keiko, Minncci Saverio, Dey A. and Scants, JH. The role of RXRβ for retinoic acid regulated gene expression in embryonal carcinoma cells. Proceedings of the American Association for Cancer Res. Vol. 35, 1994 PP668
47. Harada H., Willison K., Fujita T et al. Absence of the Type Ⅰ IFN system in EC cells: Transcriptional Activator(IRF-1) and Repressor(IRF-2) Genes Are Develop mentally regulated. Cell 63: 303-312, 1990
48. Sporn MB and Roberts A. B, Role of Retinoids in differentiation and carcinogenesis. Cancer Research. 43: 3084-3040, 1983
49. Woodworth C., gossmann B. and Craigheud J. Squamous metaplasia of respiratory tract. Possible pathogenic role in asbestos-associated bronchogenic carcinoma. Lab Invest. 48: 578-584, 1983
50. Jetten A. M., Brody, A, R., Deas M. A. and Thither S. M. (1987b). Retinoic acid and substratum regulate the differentiation of rabbit tracheal epithelial cells into squamous, and secretory phenotype. Lab. Invest, 56: 654-66451. Jetten A. M., George, M. A., Snith H. L., Vollberg T. M. Keratin eapression in relation to squamous cell differentiation in rabbit tracheal epithelial Cells: regulation by retioic acid, Exp. cell Res. 182: 622-634. 1986b
52. Smith M. A., Parkinson D. R., Cheson B. D., and Friedman M. A. Retinoids in Cancer therapy, J Clin Oncol 10: 839-864, 1992
53. Imaizumi M. and Breitman T., Retinoic Acid-induced differentiation of the human promyelocytic leukemia cell line, HL-60 and fresh human leukemia cells in primary culture: A model for differentiation inducing therapy of leuketis. Eur J Baematol 38: 289-302, 1987
54. Sidell M, Altman A, Haussler M., et al Effects of retinoic acid(RA) on the grgwth and phreotypic expression of several human neuroblastoma cell lines. Exp. Cell. Res. 148: 21-30, 1983
55. Tsokos M., Ross R., and Triche T. Neuonal, Schwannian and melanocytic differentiation of human neuroblastoma cells in vitro, in Evans A., D'Angio G., Seeger R(eds), Advances in Neuro- blastoma Research. New York, NY, Liss, 1985, pp: 55-68
56. Meyskene F., Alberts D. and Salmon S.: Effect of 13-cis-retinoic acid and 4 -hydroxyphenyl-all-trans-retinamide on human tumor colony formation in soft agar. Int J Cancer 32: 295-299, 1983
57. Glick A., Mc. Cune B., Abdulkarem N., et al. Compiex regulation of TGFβ expression by retinoic acid in the Vitamin A deficient rat. Development 111: 1081-1086, 1991
58. Mahrle G. and Thiele B: Retineids in cutaneous T cell-lymphomas. Dermatologica 175: 145-150, 1987 (Suppl Ⅰ)
59. Breitman T. and He R. Combination of relinoic acid with eithor sodium butyrate, dimethylsulfoxide, of hexamelhylene hisacetamide synergistically induce differentiation of the human myeloid leukemia cell line HL-60. Cancer Res. 50: 6268-6273, 1990
60. Tobler A. Munker K. and Heitjan D. In vitro interaction of recombinant tutor necrosis factor alpha and all-trans- rctinoic acid with normal and leukemic hematopoietic cells Blood. 70: 1940-1946, 1987
61. Duvall E and Wyllie A, Death and the cell Immunal Tody, 7: 115-119, 198662. Martin S., Bradley J, and Cotter T. HL-60 cells induced to differentiats towards nentrophils subsequently die via apoptosis. Clin Exp Immunol 79: 448-453, 1990
63. Chomienne C., Ballerini P., Balitrand N and Degos L et al. All trans Retinoic acid in auts Promyelocytic leukemias. Ⅱ. In vitro: Structure-function Relationship Blood. 76: 1710-1717, 1990
64. Rotello R., Lieberman R. and Purchio, et al. Coordinated regulation of apoptosis and cell proliferation by transforming growth factor β_1 in cultured uterine epithelial cells. Proc Natl Acad Sci 88: 3412-3415, 1991
65. Martin S. J., Green D. R. and Cotter T. G. Dicing with Death: dissecting the components of the apoptosis machinery. TIBS 19: 26-30, 1994
66. Zhang LX, Mills K. J., Collin S. J. and Jetten A. M. Evidence for the involvement of an RAR-α dependent signaling pathway in the induction of tissue transglutaminase and apoptosis by Retinoids. J Bio Chem. 270(12): 1-8, 1995
67. Kurie J. M., Lippman S. M. and Hong W. K. Potential of getinoids in Cancer prevention Cancer Treatment Reviews. 20: 1-10 1994
68. Lippman S. M., Bonner S. E. and Hong W. K. Retinoid chemoprevention studies in upper aerodigestive tract and lung carcinogenesis. Cancer Res. (Suppl) 54: 2025s-2028s, 1994
69. Lotan R. Retinoic acid receptors and retinoids-regulated differentiation markers as intermediate endpoints in chemoprevention. Proceedings of the American association for cancer Res. Vol. 35, pp: 684, 1994
70. Lippman S. M., Kessler J. F. and Meyskens Jr FL. Retinoids as preventive and therapeutic anticancer agents (Part Ⅱ). Cancer Treatment Reports. 71(5): 493-515, 1987
71. Kraemer K. H., Di Giovanna J. J., Peck G. L., et al. Prevention of skin cancer in xeroderms pigmentosum with the use of isotretinoin. N Engl. J. Med. 318: 1633-1637, 1988
72. Hong W. K., Endicott J., Strong S., et al. 13-cis retinoic acid in the treatment of oral lenkoplakia N. Engl. J. Med. 315: 1501-1504 1986
73. Lippman S. M., Bataskis J. G., and Hong W. K. et al Low- dose isotretinoin therapy with heat-carotene for prevention of oral carcinogenesis. N. Engl. J, Med. 328: 58-59, 199374. Meyskens F. L. Jr and Surwit E. S. Clinical experience with topical tretinoin in the treatment of cervical dysplasia. J. AM Acid Dermatol. 15: 826-829, 1986
75．蔡海英等：新维生素甲酸衍生物抑制小鼠前胃鳞状上皮癌变的研究 药学学报16：648，1981
76．林培中等：N-(4-磺氨基苯基)维生素甲酰胺等三种新的维生素甲酸衍生物抑制小鼠前胃上皮增生癌变的作用 中国医学科学院学报 6(3)：223-224，1984
77．林培中、张金生等：食管癌前病变的药物阻断性治疗——抗癌乙片维胺酯和核黄素三年和五年的阻断放果 中国医学科学院学报 12(4)：235，1990
78. Hong W. K., Lippman S. M., Itri, L. M. et al Prevention of second primary tumors with isotretinoiu in squamous cell carcinoma of the head and neck. N. Engl. J. Med. 323: 795-801, 1990
79. Pastorino U., Infante M., Maioli M., et al. Adjuvant treatment of stage I lung cancer with high-dose vitamin A. J. Clin. Oncol. 11: 1216-1222, 1993
80. Studer (?). E., Biederman C., Chollet D., et al. Prevention of (?)urrent superficial bladder tumors by oral etretinate. J. Urol 131: 47-49, 1984
81. Huang Meng-er, Ye Yu-chen and Wang Zhen-yi. Use of all-trans retinoic Reid in the treatment of acute prosyelocytic leukemia. Blood. 72: 567-572, 1988
82. Warrel R., Frankel S., Miller W., et el. Differentiation therapy of acunte promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N Engl. J. Med. 324: 1385-1393, 1991
83. Chen S-J, Zhu Y-J, Toug J-H, et al. Rearrangement in the second iatrons of the RARA gene are present in a large majority of patients with acnte promyelocytic leukemia and are used as molecular marker for retinoic acid-induced leukemic cell differentiation. Blood. 78: 2696-2701, 1991
84. Lippman S., Parkinson D., Itri L., et al. 13-cis -retinoic acid plus interferon alpha-2α: effctive combination for advanced squamous cell carcinoma of the skin. J. Natl. Cancer Inst. 84: 235-241, 1992
85. Lippman S., Kavanaugh J., Paredes-Espinoza M. et al. 13-cis -retinoic acid plus interferon-alpha-2a: highly active systemic therapy for squamous cell carcinoma of the cervix. J. Natl. Cancer Inst. 84: 241-245, 199286. Lippman S. M, Kessler J. F. and Meyskens Jr, FL. Retinoid as preventive and therapcutic anticancer agents (Part Ⅰ). Cancer Treatment Reports. 71(4): 391-405, 1987
87. Lohnes D., Dierich A., Ghyselinck N., et al. Retinoid receptors and binding proteins. J of Cell Science, suppll 6: 69-T6, 1992
88. Maden M., Ong D. E., Summerbell D., et al. Spatial distribution of cellular proteins binding to retinoic acid in the chick limb bud. Nature 335: 733-735, 1988
89. Takase S., Ong D. E., and Chytil F. Transfer of RA from its complex with cellular retinoic acid binding protein to the nucleus. Arch Biochem. Biophys. 247: 328, 1988
90. Maden M., Ong D. E., Summerbell D., et al. Spatial distribution of cellular proteins binding to r etinoic acid in the chick limb budl. Nature 335: 733-735, 1988
91. Christine C. Molecular features of acute promyelocytic leukemic cells linked to cell growth differentiation and survival. Proceedings of the American Association for Cancer research. Vol. 35, PP669, March, 1994
92. Petkovich, M., Brand NT, Krust A, et al. A human retinoic acid receptor which belongs to the family of nuclear receptor. Nature 330: 444-450, 1987
93. Brand N, Petkovich M, Krust A, el al. Identification of a second human retinoic acid receptor. Nature 322, 850-853, 1988
94. Krust A, Kastner P, Petkovich M, et al. A Third human retinoic acid receptor, hRAR-gamma. Proc. Natl Acad Sci. USA 86: 5310-5314
95. Mattei MG, Rivixere M, Krust A, et al. Chromosomal assignment of retinoic acid receptor (RAR) genes in the human, monse and rat genes. Genomics. 10: 1061-1069, 1991
96. Hangelsdorf, DJ, Gas ES, Dyck JA et al. Nuclear receptor that identifies a novel retinoic acid response way, Nature 345, 224-229, 1990
97. Hoopes, CW, Taheto M, Ozato K et al. Mapping of the mouse Rxr loci encoding nuclear retinoid X receptors RXRα, RXRβ, and RXRγ. Genomics. 14: 611-617, 1992
98. Glass CK, Direuzo J, Kuroknwa R and HAN ZH Regulation of gene expression by retinoic acid receptors. DNA and Cell Biology. 10(9): 623-638, 199199. Richard AH, Mangelsdorf DJ, Evans RM and Thatler C, 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor. Cell 67: 397-406, 1992
100. Zelent A, Mendelsohn C, Kastner P, et al, Differentially expressed isoform of the mouse retinoic acid receptor beta are generated by usage of two promoters and alternative splicing. EMBO J. 10: 71-81, 1991
101. Leroy P., Krust A, and Zelent A et al. Mutiple isoforms of the mouse retinoic acid receptor α are generated by alternative splicing and differential induction by retinoic acid. EMBO J 10 (1991a): 59-69.
102. De The, H., Marchio, A, Tiollais P and Dejenn A. A novel steroid thyroid hormone receptor related gene inappropriately expressed in human. hepato-cellular carcinoma. Nature. 330: 667-670. 1987
103. Zelent A, Krust A, Petkovich M et al. Cloning of murine α and β retinoic acid receptors and a novel receptor γ predominantly expressed in skin Nature 339: 714-717, 1989
104. De The, H, Vivanco-Ruiz, M. M., TioLLais, P. et al. Identification of a retinoic acid responsive element in the retinoic acid receptor beta anne. Nature 343: 177-180, 1990b.
105. Larosa, G. J., and Gudas, L. J. Early retinoic acid- induced F9 teratocarcinoma stem cell gene ERA-1: Alternate splicing creates transcripts for a homeobox-containing protein and one lacking the homeobox. Mol. Cell Biol. 8: 3906-3917, 1988
106. Duester, G., Shean, M. L., McBride N. S, et al. getinoic acid response element in the human alcohol dehydrogenase gene ADH3: Implications for regulation of retinoic acid synthesis. Mol. Cell Biol 11: 1638-1646, 1991
107. Bado, G., Santisteban P and Aranda A Retinoic acid regulates growth hormone gene expression. Nature 339: 231-234, 1989
108. Kim JS, Stack PA and Lotan R. Suppression by retinoic acid of epidermal growth factor receptor antophos- phorylation and glycosylation in cultured human head and neck squamous carcinoma cell. J Nail Cancer Inst Monet. 13: 101-110, 1992
109. Visions GW, Gold JD, Putkovich M and Gudas LJ. A retinoic acid responsive element is present in the 5' flanking region of the lamini B1 genc. Proc. Natl Acad Sci USA 86: 9099-9103, 1989110. Taylor CW, Kim YS and Yeoman LC, Sensitivity of nuclear c-myc levels and induction to differentiation-inducing agents inhuman colon tumor cell lines, Cancer Lett, 62(2): 95-105, 1992
111. Feng Luo, Wang XQ, Wu M et al.: A strategy for isolating differention-inducing complementary DNAs from human esophageal cancer cell line treated with retinoic acid. Science in Chinese (series B) 35(4): 445,1992
112．闫水忠，付明，王秀琴，吴旻 RA538基因对人食管癌细胞c-myc基因表达的降调节作用 中国首届人类基因诊断，治疗与预防研讨会论方集．1994年11月，北京，PP22
113. Schule R, Rangarajan P and Evans RM. Retinoic acid is a negative regulator of AP-1-responsive genes. Proc Natl Acad Sci. USA 88:6092-6096,1991
114. Jaffey P, Chan L-N Shan JG et al. Retinoic acid Inhibition of Serum-induced c-fos transcription in a fibrosarcoma cell line. Cancer Res 52:2384-2388, 1992
115. Desbois C, Fain B, Guilhot C and Samarut J. V-erbA oncogene abrogates growth inhibition of chicken embryo fibroblasts induced by retinoic acid. Oncogene 6: 2129-2135,1991
116. Mangelsdorf, DJ, Umesono k, Kliewer SA et al. A direct repeat in the cellular retinol-binding protein type Ⅱ gene confers differential regulation ty RXR and RAR. Cell 66: 555-561,1991
117. Rottman, J. N., Widom RL, Nadal-Ginard B, et al. A retinoic acid-responsive element in the apolipoprotein AI gene distinguishes between two different retinoic acid response pathways. Mol. Cell Biol 11:3814-3820,1991
118. Unesono K, Giguere V, Glass CK et al. Retiuoice acid and thyroid hormone induce gone expression through a common responsive element. Nature 336:262-265,1988
119. Hoffmann B, Lehmamn JM, Zhang XK et al. A retinoic acid receptor-specific element controls the retinoic acid receptorbeta promoter. Mol Endocrinol 4:1727-1736,1990
120. Umesono, K., Murakami K K, Thompson C. C and Evans R. M. Direct repeats as selective response elements for the thyroid hormone, retinoic acid, and vitamin D3 receptor. Cell 65:1255-1266,1991121. Vasios GW, Gold JD, Petkovich M. et al. A retinoic acidreaponsive element is present in the 5' flanking region of the laninin B1 gene. PNAS 86: 9099-9103, 1989
122, Richard S and Zingg R. Identification of a retinoic acid response element in the human oxytocin promoter. J Biol Chem, 266: 21428-21433,1991
123. Glass CK, Lipkin SM, Devary OV and Rosenfeld MG. Positive and negative regulation of gene transcription by a retinoic acid-thyroid hormone receptor heterodimer. Cell 59:697-708,1989
124. Glass CK, Devary OV and Rosenfeld MG. Multiple cell type-specific proteins differentially regulate target sequence recognition by the alpha retinoic acid receptor. Cell 63:729-738,1990
125. Gudas L J. Retinoids, Retinoid-responsive genes, cell differentiation, and cancer. Cell Growth & Differentiation 3:655-662,1992
126. De The' H, Chomienne C, Lanotte M, et al. The t(15;17) translocation of acute pronyelocytic leukaemia fuses the retinoic acid receptor α gene to a novel transcribed locus. Nature. 347:558-561,1990
127. Kakiznka A, Miller WH Jr, Umesono K, et al: Chromosomal translocation t(15;17) in human acute pronyelocytic leukemia fuses RARα with a novel putative transcription factor, PML. Cell 66:663-674,1991
128．耿解萍，童建华，董硕等：急性早幼粒细胞白血病-维甲酸α受体融合基因异的构体的分子生物学研究 中华医学杂志 73(4)：197-200，1993
129. Grignani F, Ferrucci PF, Testa U, et al. The acute promyelocytic leukemia-specific PML-KAR α fusion protein inhibits differentiation and promotes survival of myeloid precursor cells. Cell 74: 423-431,1993
130．陈竺：急性早幼粒细胞白血病(APL或AML-M3)基因研究的若干进展；第三次全国医学遗传学学术会议文摘汇编 1994，大连，PP49
131. Hu L, Crowe DL, Rheinwald JG, et al. Abnormal expression of retiuoic acid receptors and keratin 19 by human oral and epidermal equamous cell carcinoma cell lines. Cancer Rea, 51: 3972-3981,1991132. Gebert JF, Moghal N, Frangioni Jr, et al. High frequency of retinoic acid receptor β abnormalities in human lung cancer Oncogene 6: 1859-1868, 1991
133. Zou CP, Clifford JL, Xu XC et al. Modulation by Reticnoic Acid(RA) of squamous cell differentiation, cellular RA-binding protein, and Nuclear RA receptors in human head and neck squamous cell carcinoma cell lines. Cancer Res 54: 5479-5487,1994
134. Swisshelm K, Ryan K, Sager R et al. Down-regulation of retinoic acid receptor β in mammary carcinoma cell lines and its up- regulation in senescing, normal mammary epithelial cells. Cell Growth & Differentiation, 5: 133-144,1994
2. Knndson AG. Antioncogeues and human cancer. Proc Natl Acad Sci USA 9: 10914-10921, 1993
3. Weiberg RA. The integration of molecular genetics into cancer management. Cancer 70: 1653-1658, 1992
4．赵晓航，王秀琴，彭仁玲，闰水忠，吴旻 c-myc反义RNA特异性诱发人食管癌细胞程序性死亡 中国科学B辑 23卷，11期：1185-1192，1993
5. Zhang W-W. Fang. XM, Mazur W, et al. Hingh-efficiency gene transfer and high-level expression of wild-type p53 in human lung cancer cells mediated by recombinant adenovirus, Gene cancer therapy. 1(1): 5-13, 1994
6. Fujiwara T, Grimm D, Mukhopadhyay T, et al. Induction of chemosensitivity in human lung cancer in vivo by adenovirus-mediated transfer of the wild-type p53 gene. Cancer Res. 54: 2287-2291, 1994
7. Sachs L. Control of normal cell differentiation and the phenotypic reversion of malignancy in myeloid leukaemia Nature 274: 535-539, 1978
8．冯骆，王秀琴，吴旻等，从人食管癌细胞系分离分化基因的新方法 中国科学(B辑)，20：1059-1066，1991
9．杨晓光，丁芳，郑文岭，王秀琴，吴旻 cDNA从538的表达诱导亲本恶性细胞系发生终末分化和凋亡．中国医学科学院学报16卷，4期：251-253，1994
10．杨晓光，任力强，丁芳，郑文岭，王秀琴，周传农，吴旻 cDNA RA538对三种人癌细胞系抑制作用的研究，中国医学科学院学报 16卷，第4期：254
11．黎伯铨，维甲酸诱导的人肺腺癌细胞促分化基因的克隆，第三军医大学，博士论文，1995年5月
12．金冬雁，黎孟枫等译 分子克隆实验指南，萨姆布鲁克，弗里奇，曼尼阿蒂斯著 科学出版社，1992
13. Chomezynski P and Sacchi N. Single-step method of RNA isolation by acid guanidium thicocyanate-phenol-chloroform extraction. Anal Biochem. l62: 156-159, 198714．卢圣栋主编，现代分子生物学实验技术，高等教育出版社，1993，pp109
15．林万明主编 核酸探针杂交实验技术，中国科学技术出版社 1991年，北京
16．雷薇，吴旻 维甲酸对细胞增殖分化调节的分子机制，国外医学分子生物学分册16(2)：83-86，1994
17. Mulligan RC and Beig P. Selection for animal cells that express the Escherichia coli gene coding for xanthine-guanine phosphoribosyl transferase. Proc, Natl, Acad. Sci. USA. 78(4): 2072-2076, 1981
18. Chapman AB, Costello MA, Riugold GM et al. Amplification and hormone-regulated expression of a monse mammary tumor virus-Eco gpt fusion plasmid in mouse 3T6 cells. Mol. Cell. Biol. 3(8): 1421-1429, 1983
19. Klessing DF, Brough DE and Cleghon V. Introduction, stable integration and controlled expression of a chimeric adenovirus gene whose product is toxic to the recipient human cell. Mol. Celi. Biol. 4(7): 1354-1362, 1984
20. Schraml P, Shipman R, Colobi M, et al. Identification of genes differentially expressed in normal lung nod non-small cell lung carcinoma tissue. Cancer Res. 54: 5236-5240, 1994
21. Steinnan RA, Hoffman B, Ira A et al, Iaduction of p21 (WAF-1/CIP1)during differentiation. Oncogene. 9: 3389-3396, 1994
22. Jiang HP, Lin J, Su Z et al. Induction of differentiation in human promyelocytic RL-60 leukemia cells activates p21, WAF1/CIP1. Oncogene. 9: 3397-3406, 1994
23. Matin SJ, Green DR and Cotter TG. Dicing with death: dissecting the components of the apoptosis mechinery. TIBS. 19: 26-30, 1994
24. Williams GT et al. Prosrammed cell death: apoptosis and oacogeuesis. Cell, 65: 1097, 1991
25. Eastman A. Activation of programmed cell death by anticancer agents: cisplatin as a model system. Cancer Cells. 2: 275-280, 1990
26. Furuya Y and Isaacs JT. Proliferation-indepen-dent programmed cell death as a therapeutic target for prostate cancer. The Cancer Bulletin. 46(2): 173-179, 1994
27. Wyllie AH. Apoptosis(The 1992 Frank Rose Memorial Lecture). Br. J. Cuncer. 67: 205-208, 199328. Kosa K, Megers K, and Deluca LM. Transformation of NIH3T3 cells with ras oncogenes abrogated the retinoic acid induction of tissue transglutaminase. Biochem. Biophys. Res. Comm. 196(3): 1025-1033, 1993
29．黎伯铨，雷薇，张雪燕，王秀琴，毛宝龄，吴旻 维甲酸激活的人肺腺癌细胞促分化基因的克隆和鉴定。中国首届人类基因诊断，治疗与预防研讨会论文集，pp17，1994，北京
30. Foo- Min Liew and Kiyofuni Yamanishi. Regulation of transglntaminase I gene expression by 12- 0-tetradecanoylphorbol-13-acetate, dexame- thasone and retinoic acid in cultured human kers- tinocytes. Exp. Cell Res. 202: 310-315, 1992
31. Nervi C, Voliberg TM, Chambon P and Jetten AM. Expression of nuclear retinoic acid receptors in normal tracheobronchial cells and in lung carcinoma cells. Exp. Cell Res. 195: 165-170, 1991
32. Kalemlerian GP, Jasti RK, Celano P, et al. All-trans -retinoic acid alters aye gene expression and inhibits in vitro progression in small cell lung cancer. Cell Growth & Differentiation 5: 55-60, 1994
33. Eguchi Y, Itoh T and Tomizawa J-I. Antisense RNA. Annu. Rev Biochem. 60: 631-652, 1991
34. Okubo K, Hori N, Matsubara K et al. Large scale cDNA sequencing for analysis of quantita- tire and qualitative aspects of gene expression. Nature Genetics. 2: 173-179, 1992
35. Adams MD, Kerlavage AR, Veter JC et al. 3400 new expressed sequence tags identify diversity of transcripts in human brain. Nuture Genetics. 4: 256-267, 1993
36. Dusrmmond TC. The nomenclature of the so- called accessory food factor(vitamins). Biochem J. 14: 660, 1920
37. Wolbach, S. B., and Howe, P. R., Tissue chdanges following deprivation of fat soluble A vitamin. J. Exp. Med., 42: 753-777, 1925
38. ChytilF: Retinoic acid: Biochemistry and metabolism. J. Am Acad Dermatol 15: 741-747, 1986
39. Cope F. and Wills J. Retinoid receptor antisense DNAs inhibit alkaline phosphatase induction and clonogenicity in malisnant keratinocytes. Proc. Nutl kcad Sci USA 86: 5590-5594, 198940. Napoli J., Pramanik B. Willams J. et al. Quantification of retinoicd acid by gas-liquid chromatography-mass spectometry total versus all-trans-retinoic acid in human plasma. J. Lipid Res. 26: 387-392, 1985
41. Thaller C. and Eichele G. Identification and spatial distribution of retinoids in the developing chick limb bud. Nature. 327: 625-628, 1987
42. Tickle C. Retinoic acid and chick limb bud development. Development. 1: 113-121, 1991(suppl)
43. Durston A, Timmermans J. and Hare W. el al. Retinoic acid causes an anteroposterior transformation in the developing central nervous system. Nature 340: 140-144, 1989
44. Amatruda T. and Keoffler H. Retinoids and cells of the hematopoietic system, in Sherman M. (ed): Retinoids and cell differentiation. Boca Raton, FL, CRC Press, 1986, pp: 79-103
45. Doner D and Keoffler H. Retinoie acid enhances colony-stimulating factor- induced elonal growth of normal human myeloid progenitor cells in vitro. Exp. Cell Res. 138: 193-198, 1982
46. Ozato Keiko, Minncci Saverio, Dey A. and Scants, JH. The role of RXRβ for retinoic acid regulated gene expression in embryonal carcinoma cells. Proceedings of the American Association for Cancer Res. Vol. 35, 1994 PP668
47. Harada H., Willison K., Fujita T et al. Absence of the Type Ⅰ IFN system in EC cells: Transcriptional Activator(IRF-1) and Repressor(IRF-2) Genes Are Develop mentally regulated. Cell 63: 303-312, 1990
48. Sporn MB and Roberts A. B, Role of Retinoids in differentiation and carcinogenesis. Cancer Research. 43: 3084-3040, 1983
49. Woodworth C., gossmann B. and Craigheud J. Squamous metaplasia of respiratory tract. Possible pathogenic role in asbestos-associated bronchogenic carcinoma. Lab Invest. 48: 578-584, 1983
50. Jetten A. M., Brody, A, R., Deas M. A. and Thither S. M. (1987b). Retinoic acid and substratum regulate the differentiation of rabbit tracheal epithelial cells into squamous, and secretory phenotype. Lab. Invest, 56: 654-66451. Jetten A. M., George, M. A., Snith H. L., Vollberg T. M. Keratin eapression in relation to squamous cell differentiation in rabbit tracheal epithelial Cells: regulation by retioic acid, Exp. cell Res. 182: 622-634. 1986b
52. Smith M. A., Parkinson D. R., Cheson B. D., and Friedman M. A. Retinoids in Cancer therapy, J Clin Oncol 10: 839-864, 1992
53. Imaizumi M. and Breitman T., Retinoic Acid-induced differentiation of the human promyelocytic leukemia cell line, HL-60 and fresh human leukemia cells in primary culture: A model for differentiation inducing therapy of leuketis. Eur J Baematol 38: 289-302, 1987
54. Sidell M, Altman A, Haussler M., et al Effects of retinoic acid(RA) on the grgwth and phreotypic expression of several human neuroblastoma cell lines. Exp. Cell. Res. 148: 21-30, 1983
55. Tsokos M., Ross R., and Triche T. Neuonal, Schwannian and melanocytic differentiation of human neuroblastoma cells in vitro, in Evans A., D'Angio G., Seeger R(eds), Advances in Neuro- blastoma Research. New York, NY, Liss, 1985, pp: 55-68
56. Meyskene F., Alberts D. and Salmon S.: Effect of 13-cis-retinoic acid and 4 -hydroxyphenyl-all-trans-retinamide on human tumor colony formation in soft agar. Int J Cancer 32: 295-299, 1983
57. Glick A., Mc. Cune B., Abdulkarem N., et al. Compiex regulation of TGFβ expression by retinoic acid in the Vitamin A deficient rat. Development 111: 1081-1086, 1991
58. Mahrle G. and Thiele B: Retineids in cutaneous T cell-lymphomas. Dermatologica 175: 145-150, 1987 (Suppl Ⅰ)
59. Breitman T. and He R. Combination of relinoic acid with eithor sodium butyrate, dimethylsulfoxide, of hexamelhylene hisacetamide synergistically induce differentiation of the human myeloid leukemia cell line HL-60. Cancer Res. 50: 6268-6273, 1990
60. Tobler A. Munker K. and Heitjan D. In vitro interaction of recombinant tutor necrosis factor alpha and all-trans- rctinoic acid with normal and leukemic hematopoietic cells Blood. 70: 1940-1946, 1987
61. Duvall E and Wyllie A, Death and the cell Immunal Tody, 7: 115-119, 198662. Martin S., Bradley J, and Cotter T. HL-60 cells induced to differentiats towards nentrophils subsequently die via apoptosis. Clin Exp Immunol 79: 448-453, 1990
63. Chomienne C., Ballerini P., Balitrand N and Degos L et al. All trans Retinoic acid in auts Promyelocytic leukemias. Ⅱ. In vitro: Structure-function Relationship Blood. 76: 1710-1717, 1990
64. Rotello R., Lieberman R. and Purchio, et al. Coordinated regulation of apoptosis and cell proliferation by transforming growth factor β_1 in cultured uterine epithelial cells. Proc Natl Acad Sci 88: 3412-3415, 1991
65. Martin S. J., Green D. R. and Cotter T. G. Dicing with Death: dissecting the components of the apoptosis machinery. TIBS 19: 26-30, 1994
66. Zhang LX, Mills K. J., Collin S. J. and Jetten A. M. Evidence for the involvement of an RAR-α dependent signaling pathway in the induction of tissue transglutaminase and apoptosis by Retinoids. J Bio Chem. 270(12): 1-8, 1995
67. Kurie J. M., Lippman S. M. and Hong W. K. Potential of getinoids in Cancer prevention Cancer Treatment Reviews. 20: 1-10 1994
68. Lippman S. M., Bonner S. E. and Hong W. K. Retinoid chemoprevention studies in upper aerodigestive tract and lung carcinogenesis. Cancer Res. (Suppl) 54: 2025s-2028s, 1994
69. Lotan R. Retinoic acid receptors and retinoids-regulated differentiation markers as intermediate endpoints in chemoprevention. Proceedings of the American association for cancer Res. Vol. 35, pp: 684, 1994
70. Lippman S. M., Kessler J. F. and Meyskens Jr FL. Retinoids as preventive and therapeutic anticancer agents (Part Ⅱ). Cancer Treatment Reports. 71(5): 493-515, 1987
71. Kraemer K. H., Di Giovanna J. J., Peck G. L., et al. Prevention of skin cancer in xeroderms pigmentosum with the use of isotretinoin. N Engl. J. Med. 318: 1633-1637, 1988
72. Hong W. K., Endicott J., Strong S., et al. 13-cis retinoic acid in the treatment of oral lenkoplakia N. Engl. J. Med. 315: 1501-1504 1986
73. Lippman S. M., Bataskis J. G., and Hong W. K. et al Low- dose isotretinoin therapy with heat-carotene for prevention of oral carcinogenesis. N. Engl. J, Med. 328: 58-59, 199374. Meyskens F. L. Jr and Surwit E. S. Clinical experience with topical tretinoin in the treatment of cervical dysplasia. J. AM Acid Dermatol. 15: 826-829, 1986
75．蔡海英等：新维生素甲酸衍生物抑制小鼠前胃鳞状上皮癌变的研究 药学学报16：648，1981
76．林培中等：N-(4-磺氨基苯基)维生素甲酰胺等三种新的维生素甲酸衍生物抑制小鼠前胃上皮增生癌变的作用 中国医学科学院学报 6(3)：223-224，1984
77．林培中、张金生等：食管癌前病变的药物阻断性治疗——抗癌乙片维胺酯和核黄素三年和五年的阻断放果 中国医学科学院学报 12(4)：235，1990
78. Hong W. K., Lippman S. M., Itri, L. M. et al Prevention of second primary tumors with isotretinoiu in squamous cell carcinoma of the head and neck. N. Engl. J. Med. 323: 795-801, 1990
79. Pastorino U., Infante M., Maioli M., et al. Adjuvant treatment of stage I lung cancer with high-dose vitamin A. J. Clin. Oncol. 11: 1216-1222, 1993
80. Studer (?). E., Biederman C., Chollet D., et al. Prevention of (?)urrent superficial bladder tumors by oral etretinate. J. Urol 131: 47-49, 1984
81. Huang Meng-er, Ye Yu-chen and Wang Zhen-yi. Use of all-trans retinoic Reid in the treatment of acute prosyelocytic leukemia. Blood. 72: 567-572, 1988
82. Warrel R., Frankel S., Miller W., et el. Differentiation therapy of acunte promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N Engl. J. Med. 324: 1385-1393, 1991
83. Chen S-J, Zhu Y-J, Toug J-H, et al. Rearrangement in the second iatrons of the RARA gene are present in a large majority of patients with acnte promyelocytic leukemia and are used as molecular marker for retinoic acid-induced leukemic cell differentiation. Blood. 78: 2696-2701, 1991
84. Lippman S., Parkinson D., Itri L., et al. 13-cis -retinoic acid plus interferon alpha-2α: effctive combination for advanced squamous cell carcinoma of the skin. J. Natl. Cancer Inst. 84: 235-241, 1992
85. Lippman S., Kavanaugh J., Paredes-Espinoza M. et al. 13-cis -retinoic acid plus interferon-alpha-2a: highly active systemic therapy for squamous cell carcinoma of the cervix. J. Natl. Cancer Inst. 84: 241-245, 199286. Lippman S. M, Kessler J. F. and Meyskens Jr, FL. Retinoid as preventive and therapcutic anticancer agents (Part Ⅰ). Cancer Treatment Reports. 71(4): 391-405, 1987
87. Lohnes D., Dierich A., Ghyselinck N., et al. Retinoid receptors and binding proteins. J of Cell Science, suppll 6: 69-T6, 1992
88. Maden M., Ong D. E., Summerbell D., et al. Spatial distribution of cellular proteins binding to retinoic acid in the chick limb bud. Nature 335: 733-735, 1988
89. Takase S., Ong D. E., and Chytil F. Transfer of RA from its complex with cellular retinoic acid binding protein to the nucleus. Arch Biochem. Biophys. 247: 328, 1988
90. Maden M., Ong D. E., Summerbell D., et al. Spatial distribution of cellular proteins binding to r etinoic acid in the chick limb budl. Nature 335: 733-735, 1988
91. Christine C. Molecular features of acute promyelocytic leukemic cells linked to cell growth differentiation and survival. Proceedings of the American Association for Cancer research. Vol. 35, PP669, March, 1994
92. Petkovich, M., Brand NT, Krust A, et al. A human retinoic acid receptor which belongs to the family of nuclear receptor. Nature 330: 444-450, 1987
93. Brand N, Petkovich M, Krust A, el al. Identification of a second human retinoic acid receptor. Nature 322, 850-853, 1988
94. Krust A, Kastner P, Petkovich M, et al. A Third human retinoic acid receptor, hRAR-gamma. Proc. Natl Acad Sci. USA 86: 5310-5314
95. Mattei MG, Rivixere M, Krust A, et al. Chromosomal assignment of retinoic acid receptor (RAR) genes in the human, monse and rat genes. Genomics. 10: 1061-1069, 1991
96. Hangelsdorf, DJ, Gas ES, Dyck JA et al. Nuclear receptor that identifies a novel retinoic acid response way, Nature 345, 224-229, 1990
97. Hoopes, CW, Taheto M, Ozato K et al. Mapping of the mouse Rxr loci encoding nuclear retinoid X receptors RXRα, RXRβ, and RXRγ. Genomics. 14: 611-617, 1992
98. Glass CK, Direuzo J, Kuroknwa R and HAN ZH Regulation of gene expression by retinoic acid receptors. DNA and Cell Biology. 10(9): 623-638, 199199. Richard AH, Mangelsdorf DJ, Evans RM and Thatler C, 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor. Cell 67: 397-406, 1992
100. Zelent A, Mendelsohn C, Kastner P, et al, Differentially expressed isoform of the mouse retinoic acid receptor beta are generated by usage of two promoters and alternative splicing. EMBO J. 10: 71-81, 1991
101. Leroy P., Krust A, and Zelent A et al. Mutiple isoforms of the mouse retinoic acid receptor α are generated by alternative splicing and differential induction by retinoic acid. EMBO J 10 (1991a): 59-69.
102. De The, H., Marchio, A, Tiollais P and Dejenn A. A novel steroid thyroid hormone receptor related gene inappropriately expressed in human. hepato-cellular carcinoma. Nature. 330: 667-670. 1987
103. Zelent A, Krust A, Petkovich M et al. Cloning of murine α and β retinoic acid receptors and a novel receptor γ predominantly expressed in skin Nature 339: 714-717, 1989
104. De The, H, Vivanco-Ruiz, M. M., TioLLais, P. et al. Identification of a retinoic acid responsive element in the retinoic acid receptor beta anne. Nature 343: 177-180, 1990b.
105. Larosa, G. J., and Gudas, L. J. Early retinoic acid- induced F9 teratocarcinoma stem cell gene ERA-1: Alternate splicing creates transcripts for a homeobox-containing protein and one lacking the homeobox. Mol. Cell Biol. 8: 3906-3917, 1988
106. Duester, G., Shean, M. L., McBride N. S, et al. getinoic acid response element in the human alcohol dehydrogenase gene ADH3: Implications for regulation of retinoic acid synthesis. Mol. Cell Biol 11: 1638-1646, 1991
107. Bado, G., Santisteban P and Aranda A Retinoic acid regulates growth hormone gene expression. Nature 339: 231-234, 1989
108. Kim JS, Stack PA and Lotan R. Suppression by retinoic acid of epidermal growth factor receptor antophos- phorylation and glycosylation in cultured human head and neck squamous carcinoma cell. J Nail Cancer Inst Monet. 13: 101-110, 1992
109. Visions GW, Gold JD, Putkovich M and Gudas LJ. A retinoic acid responsive element is present in the 5' flanking region of the lamini B1 genc. Proc. Natl Acad Sci USA 86: 9099-9103, 1989110. Taylor CW, Kim YS and Yeoman LC, Sensitivity of nuclear c-myc levels and induction to differentiation-inducing agents inhuman colon tumor cell lines, Cancer Lett, 62(2): 95-105, 1992
111. Feng Luo, Wang XQ, Wu M et al.: A strategy for isolating differention-inducing complementary DNAs from human esophageal cancer cell line treated with retinoic acid. Science in Chinese (series B) 35(4): 445,1992
112．闫水忠，付明，王秀琴，吴旻 RA538基因对人食管癌细胞c-myc基因表达的降调节作用 中国首届人类基因诊断，治疗与预防研讨会论方集．1994年11月，北京，PP22
113. Schule R, Rangarajan P and Evans RM. Retinoic acid is a negative regulator of AP-1-responsive genes. Proc Natl Acad Sci. USA 88:6092-6096,1991
114. Jaffey P, Chan L-N Shan JG et al. Retinoic acid Inhibition of Serum-induced c-fos transcription in a fibrosarcoma cell line. Cancer Res 52:2384-2388, 1992
115. Desbois C, Fain B, Guilhot C and Samarut J. V-erbA oncogene abrogates growth inhibition of chicken embryo fibroblasts induced by retinoic acid. Oncogene 6: 2129-2135,1991
116. Mangelsdorf, DJ, Umesono k, Kliewer SA et al. A direct repeat in the cellular retinol-binding protein type Ⅱ gene confers differential regulation ty RXR and RAR. Cell 66: 555-561,1991
117. Rottman, J. N., Widom RL, Nadal-Ginard B, et al. A retinoic acid-responsive element in the apolipoprotein AI gene distinguishes between two different retinoic acid response pathways. Mol. Cell Biol 11:3814-3820,1991
118. Unesono K, Giguere V, Glass CK et al. Retiuoice acid and thyroid hormone induce gone expression through a common responsive element. Nature 336:262-265,1988
119. Hoffmann B, Lehmamn JM, Zhang XK et al. A retinoic acid receptor-specific element controls the retinoic acid receptorbeta promoter. Mol Endocrinol 4:1727-1736,1990
120. Umesono, K., Murakami K K, Thompson C. C and Evans R. M. Direct repeats as selective response elements for the thyroid hormone, retinoic acid, and vitamin D3 receptor. Cell 65:1255-1266,1991121. Vasios GW, Gold JD, Petkovich M. et al. A retinoic acidreaponsive element is present in the 5' flanking region of the laninin B1 gene. PNAS 86: 9099-9103, 1989
122, Richard S and Zingg R. Identification of a retinoic acid response element in the human oxytocin promoter. J Biol Chem, 266: 21428-21433,1991
123. Glass CK, Lipkin SM, Devary OV and Rosenfeld MG. Positive and negative regulation of gene transcription by a retinoic acid-thyroid hormone receptor heterodimer. Cell 59:697-708,1989
124. Glass CK, Devary OV and Rosenfeld MG. Multiple cell type-specific proteins differentially regulate target sequence recognition by the alpha retinoic acid receptor. Cell 63:729-738,1990
125. Gudas L J. Retinoids, Retinoid-responsive genes, cell differentiation, and cancer. Cell Growth & Differentiation 3:655-662,1992
126. De The' H, Chomienne C, Lanotte M, et al. The t(15;17) translocation of acute pronyelocytic leukaemia fuses the retinoic acid receptor α gene to a novel transcribed locus. Nature. 347:558-561,1990
127. Kakiznka A, Miller WH Jr, Umesono K, et al: Chromosomal translocation t(15;17) in human acute pronyelocytic leukemia fuses RARα with a novel putative transcription factor, PML. Cell 66:663-674,1991
128．耿解萍，童建华，董硕等：急性早幼粒细胞白血病-维甲酸α受体融合基因异的构体的分子生物学研究 中华医学杂志 73(4)：197-200，1993
129. Grignani F, Ferrucci PF, Testa U, et al. The acute promyelocytic leukemia-specific PML-KAR α fusion protein inhibits differentiation and promotes survival of myeloid precursor cells. Cell 74: 423-431,1993
130．陈竺：急性早幼粒细胞白血病(APL或AML-M3)基因研究的若干进展；第三次全国医学遗传学学术会议文摘汇编 1994，大连，PP49
131. Hu L, Crowe DL, Rheinwald JG, et al. Abnormal expression of retiuoic acid receptors and keratin 19 by human oral and epidermal equamous cell carcinoma cell lines. Cancer Rea, 51: 3972-3981,1991132. Gebert JF, Moghal N, Frangioni Jr, et al. High frequency of retinoic acid receptor β abnormalities in human lung cancer Oncogene 6: 1859-1868, 1991
133. Zou CP, Clifford JL, Xu XC et al. Modulation by Reticnoic Acid(RA) of squamous cell differentiation, cellular RA-binding protein, and Nuclear RA receptors in human head and neck squamous cell carcinoma cell lines. Cancer Res 54: 5479-5487,1994
134. Swisshelm K, Ryan K, Sager R et al. Down-regulation of retinoic acid receptor β in mammary carcinoma cell lines and its up- regulation in senescing, normal mammary epithelial cells. Cell Growth & Differentiation, 5: 133-144,1994