人子宫肌瘤相关基因的克隆和研究
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摘要
子宫肌瘤是一种受多基因控制的绝经前妇女生殖道最常见的良性肿瘤
它是导致育龄期妇女行全子宫切除术的主要病因之一严重危害妇女的身心健
康本实验室采用了两种技术来克隆肌瘤中有差异表达的基因并对所克隆到
的部分基因进行了研究以期从分子水平对其发病机理有所了解
在用mRNA 差异显示法DDPCR 筛选差异基因的过程中我们用了十二对
引物将人的肌瘤和瘤旁组织进行了比较来获取差异片段并进而用反向
Northern 的方法排除了假阳性用Northern 对真阳性克隆进行了验证结果
我们从69 个DD 条带中找到了四个被Northern 所验证的cDNA 片段其中三个
在肌瘤中高表达叫L1 L2 L3 一个在瘤旁组织中高表达叫M1 L1 经克
隆并被证明是人核糖体蛋白S19 用13 种组织做Northern 分析发现它在所有
组织中都有表达且有着不同的大小病理分布提示它在腮腺囊腺癌胰腺癌
及乳腺癌中都有高表达在6 例病人中都未发现其有突变我们的结果表明它
的过量表达是组织快速生长的指标
在用抑制差减杂交法SSH 寻找肌瘤高表达的基因中我们建立了一个肌
瘤高表达基因的cDNA 片段库这个库最终被证明含有88 个基因的cDNA 片段
在用两轮反向Northern 筛过之后有二十个基因显示为在肌瘤中高表达我
们选取了其中三个基因在Northern 分析中得到验证二十个基因中有17 个是
已知基因3 个是未知功能基因它们都是首次显示出与肌瘤有关联其中一
个叫磷酯酶A2 PLA2 的基因在6 例病人中的4 例都显示出被上调而在研究
它的组织分布时发现它在前列腺睾丸心脏和骨骼肌中都有明显表达
从Genbank 中的人EST 数据库中我们通过电子克隆得到了差减库中一个
未知基因(061)接近全长的cDNA 序列(4.1kb, 包含整个编码框) 并经克隆测
序和Northern 所证实利用人类基因组数据库我们将其定位于染色体
12q24.11 并发现其由7 个外显子所组成序列分析表明它可能有两个不同的
人子宫肌瘤相关基因的克隆和研究摘要
剪接形式(4.1Kb, 2.7kb) Northern 结果证实了这个推测在16 种人的组织
中的分布研究表明它的小mRNA 形式在人睾丸中的表达量显著高于其它组织
在aa 水平上它与人的一个TNF 诱导蛋白的同源性为71 而与小鼠中一个
未知基因则达到97
As the most common reproductive tract neoplasm in premenopausal women,
Uterine Leiomyoma (UL) is a multi-gene involved benign tumor. It is the main cause
of hysterectomy for women at reproductive age, which affects their health greatly. In
our lab, we used two different techniques to clone differentially expressed genes in
leiomyoma and studied part of them, which may help us to understand the mechanism
of UL formation at molecular level.
In searching of differentially expressed genes in human uterine leiomyomas,
differential display was used with twelve pairs of primers to compare human uterine
leiomyomas with matched myometrium. False positives were eliminated by reverse
Northern analysis. Positives were confirmed by Northern blot analysis. RESULTS: [1]
Four of 69 cDNA fragments (3 up-regulated named L1, L2 & L3 and 1 downregulated
named M1 in leiomyoma) were confirmed by Northern analysis. [2]
Sequence comparison and Northern analysis proved that L1 is exactly the human
ribosome protein S19. [3] It was present ubiquitously in 13 tissues tested but in
various levels and even in different size. [4] L1 was highly expressed in parotidean
cystadenocarcinoma, pancreatic cancer and breast cancer examined. [5] No mutations
have been found in human uterine leiomyomas (n=6). CONCLUSIONS: hRPS19
overexpression might be a universal signal in rapid cell growth tissues.
In searching for differentially expressed genes in human uterine leiomyomas
(ULs), suppression subtractive hybridization was used to construct an UL up-
regulated library, which turned out to represent 88 genes. After two rounds of
screening by reverse Northern analysis, twenty genes were proved to be up-regulated,
three of them were picked up and confirmed by Northern analysis. Among the twenty
genes, seventeen of them are known genes and the other three are genes with
unknown function, which were firstly associated with UL. One gene named
Phospholipase A2 (PLA2) showed up-regulation in 4/6 of the patients and
investigation of tissue distribution indicated that it had obvious expression in prostate,
testis, liver, heart and skeletal muscle.
From human ESTs database at Genbank, we got the nearly full length cDNA
sequence (4.1Kb, full coding sequence) of a unknown gene (061) derived from
subtracted library, which is verified by sequencing and Northern results. By
comparing its sequence with human genome database, we found it having seven
exons and located it on chromosome 12q24.11. From its sequence, we deduced it had
two forms of mRNAs because of alternative splicing and Northern results proved it.
Distribution analysis among 16 human tissues indicated that its mRNA in small form
was especially abundant in testis. We found it had 71% homology with a TNF -
induced protein in human at aa level, but 97% with a unknown gene in mouse.
它是导致育龄期妇女行全子宫切除术的主要病因之一严重危害妇女的身心健
康本实验室采用了两种技术来克隆肌瘤中有差异表达的基因并对所克隆到
的部分基因进行了研究以期从分子水平对其发病机理有所了解
在用mRNA 差异显示法DDPCR 筛选差异基因的过程中我们用了十二对
引物将人的肌瘤和瘤旁组织进行了比较来获取差异片段并进而用反向
Northern 的方法排除了假阳性用Northern 对真阳性克隆进行了验证结果
我们从69 个DD 条带中找到了四个被Northern 所验证的cDNA 片段其中三个
在肌瘤中高表达叫L1 L2 L3 一个在瘤旁组织中高表达叫M1 L1 经克
隆并被证明是人核糖体蛋白S19 用13 种组织做Northern 分析发现它在所有
组织中都有表达且有着不同的大小病理分布提示它在腮腺囊腺癌胰腺癌
及乳腺癌中都有高表达在6 例病人中都未发现其有突变我们的结果表明它
的过量表达是组织快速生长的指标
在用抑制差减杂交法SSH 寻找肌瘤高表达的基因中我们建立了一个肌
瘤高表达基因的cDNA 片段库这个库最终被证明含有88 个基因的cDNA 片段
在用两轮反向Northern 筛过之后有二十个基因显示为在肌瘤中高表达我
们选取了其中三个基因在Northern 分析中得到验证二十个基因中有17 个是
已知基因3 个是未知功能基因它们都是首次显示出与肌瘤有关联其中一
个叫磷酯酶A2 PLA2 的基因在6 例病人中的4 例都显示出被上调而在研究
它的组织分布时发现它在前列腺睾丸心脏和骨骼肌中都有明显表达
从Genbank 中的人EST 数据库中我们通过电子克隆得到了差减库中一个
未知基因(061)接近全长的cDNA 序列(4.1kb, 包含整个编码框) 并经克隆测
序和Northern 所证实利用人类基因组数据库我们将其定位于染色体
12q24.11 并发现其由7 个外显子所组成序列分析表明它可能有两个不同的
人子宫肌瘤相关基因的克隆和研究摘要
剪接形式(4.1Kb, 2.7kb) Northern 结果证实了这个推测在16 种人的组织
中的分布研究表明它的小mRNA 形式在人睾丸中的表达量显著高于其它组织
在aa 水平上它与人的一个TNF 诱导蛋白的同源性为71 而与小鼠中一个
未知基因则达到97
As the most common reproductive tract neoplasm in premenopausal women,
Uterine Leiomyoma (UL) is a multi-gene involved benign tumor. It is the main cause
of hysterectomy for women at reproductive age, which affects their health greatly. In
our lab, we used two different techniques to clone differentially expressed genes in
leiomyoma and studied part of them, which may help us to understand the mechanism
of UL formation at molecular level.
In searching of differentially expressed genes in human uterine leiomyomas,
differential display was used with twelve pairs of primers to compare human uterine
leiomyomas with matched myometrium. False positives were eliminated by reverse
Northern analysis. Positives were confirmed by Northern blot analysis. RESULTS: [1]
Four of 69 cDNA fragments (3 up-regulated named L1, L2 & L3 and 1 downregulated
named M1 in leiomyoma) were confirmed by Northern analysis. [2]
Sequence comparison and Northern analysis proved that L1 is exactly the human
ribosome protein S19. [3] It was present ubiquitously in 13 tissues tested but in
various levels and even in different size. [4] L1 was highly expressed in parotidean
cystadenocarcinoma, pancreatic cancer and breast cancer examined. [5] No mutations
have been found in human uterine leiomyomas (n=6). CONCLUSIONS: hRPS19
overexpression might be a universal signal in rapid cell growth tissues.
In searching for differentially expressed genes in human uterine leiomyomas
(ULs), suppression subtractive hybridization was used to construct an UL up-
regulated library, which turned out to represent 88 genes. After two rounds of
screening by reverse Northern analysis, twenty genes were proved to be up-regulated,
three of them were picked up and confirmed by Northern analysis. Among the twenty
genes, seventeen of them are known genes and the other three are genes with
unknown function, which were firstly associated with UL. One gene named
Phospholipase A2 (PLA2) showed up-regulation in 4/6 of the patients and
investigation of tissue distribution indicated that it had obvious expression in prostate,
testis, liver, heart and skeletal muscle.
From human ESTs database at Genbank, we got the nearly full length cDNA
sequence (4.1Kb, full coding sequence) of a unknown gene (061) derived from
subtracted library, which is verified by sequencing and Northern results. By
comparing its sequence with human genome database, we found it having seven
exons and located it on chromosome 12q24.11. From its sequence, we deduced it had
two forms of mRNAs because of alternative splicing and Northern results proved it.
Distribution analysis among 16 human tissues indicated that its mRNA in small form
was especially abundant in testis. We found it had 71% homology with a TNF -
induced protein in human at aa level, but 97% with a unknown gene in mouse.
引文
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76 Chomezynski P,Sacchi N. Single-step method of RNA Isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal. Biochem 1987; 162:156-9.
77 Liang P, Averboukh L,Parade AB. Distribution and cloning of eukaryotic mRNAs by means of differential display: refinements and optimization. Nucleic Acids Res 1993; 21:3269-75.
78 Mager WH. Control of ribosomal protein gene expression. Biochim Biophys Acta 1988; 949(1):1-15.
79 Kenmochi N, Kawaguchi T, Rozen S, Davis E, Goodman N, Hudson TJ, Tanaka T,Page DC. A map of 75 human ribosomal protein genes. Genome Res 1998; 8(5):509-23.
80 Kondoh N, Schweinfest CW, Henderson KW,Papas TS. Differential expression of S19 ribosomal protein, laminin-binding protein, and human lymphocyte antigen class I messenger RNAs associated with colon carcinoma progression and differentiation.Cancer Res 1992; 52(4):791-6.
81 Suzuki K, Olvera J,Wool IG. The primary structure of rat ribosomal protein S19.Biochimie 1990; 72(4):299-302.
82 Shim C, Zhang W, Rhee CH,Lee JH. Profiling of differentially expressed genes in human primary cervical cancer by complementary DNA expression array. Clin.Cancer Res 1998; 4(12):3045-50.
83 Rhodes LD,Van-Beneden RJ. Isolation of the cDNA and characterization of mRNA expression of ribosomal protein S19 from the soft-shell clam, Mya arenaria. Gene 1997; 197(1-2):295-304.
84 Kenmochi N, Kawaguchi T, Rozen S, Davis E, Goodman N, Hudson TJ, Tanaka T,Page DC. A map of 75 human ribosomal protein genes. Genome Res 1998; 8:509- 23.
85 Nishiura H, Tanase S, Sibuya Y, Nishimura T,Yamamoto T. Determination of the cross-linked residues in homo-dimerization of S19 ribosomal protein concomitant with exhibition of monocyte chemotactic activity. Lab. Invest 1999; 79(8):915-23.
86 Shrestha A, Horino K, Nishiura H,Yamamoto T. cquired immune response as a consequence of the macrophage-dependent apoptotic cell clearance and role of the monocyte chemotactic S19 ribosomal protein dimer in this connection. Lab. Invest1999; 79(12):1629-42.
87 Willig TN, Draptchinskaia N, Dianzani I, Ball S, Niemeyer C, Ramenghi U, Orfali K, Gustavsson P, Garelli E, Brusco A, Tiemann C, Perignon JL, Bouchier C, Cicchiello L, Dahl N, Mohandas N,Tchernia G. Mutations in ribosomal protein S19 gene and diamond blackfan anemia: wide variations in phenotypic expression. Blood 1999; 94(12):4294-306.
88 Diatchenko L, Lau YF, Campbell AP, Chenchik A, Moqadam F, Huang B,Lukyanov S, Lukyanov K, Gurskaya N, Sverdlov ED, Siebert PD. Suppression subtractive hybridization: a method for generating differentially regulated or tissuespecific cDNA probes and libraries. Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):6025-30
89 Simons M, Wang M, McBride OW, Kawamoto S, Yamakawa K, Gdula D,Adelstein RS, Weir L. Human nonmuscle myosin heavy chains are encoded by two genes located on different chromosomes. Circ Res. 1991 Aug;69(2):530-9
90 Yang DC, Wang F, Elliott RL, Head JF. Expression of transferrin receptor and ferritin H-chain mRNA are associated with clinical and histopathological prognostic indicators in breast cancer. Anticancer Res. 2001 Jan-Feb;21(1B):541-9
91 Woodman P. Vesicle transport: more work for the Rabs? Curr Biol. 1998 Mar12;8(6):R199-201. Review
92 Gerdes HH, Rosa P, Phillips E, Baeuerle PA, Frank R, Argos P, Huttner WB. The primary structure of human secretogranin II, a widespread tyrosine-sulfated secretory granule protein that exhibits low pH- and calcium-induced aggregation. J Biol Chem 1989 Jul 15;264(20):12009-12015
93 Leitner B, Schneitler C, Klocker H, Volknandt W, Zimmermann H, Winkler H,Fischer-Colbrie R. Formation and sequence analysis of secretoneurin, a neuropeptide derived from secretogranin II, in mammalian, bird, reptile, amphibian and fish brains. Neurosci Lett 1998 May 29;248(2):105-108
94 kobayashi S, Kohda T, Miyoshi N, Kuroiwa Y, Aisaka K, Tsutsumi O, Kaneko-Ishino T, Ishino F. Human PEG1/MEST, an imprinted gene on chromosome 7. Hum. Mol. Genet 1997;6:781-6
95 Pedersen IS, Dervan PA, Broderick D, Harrison M, Miller N, Delany E, O'Shea D,Costello P, McGoldrick A, Keating G, Tobin B, Gorey T, McCann A. Frequent loss of imprinting of PEG1/MEST in invasive breast cancer. Cancer Res 1999 Nov 1;59(21):5449-5451
96 Billin AN, Eilers AL, Queva C, Ayer DE. Mlx, a novel Max-like BHLHZip protein that interacts with the Max network of transcription factors. J Biol Chem 1999 Dec 17;274(51):36344-36350
97 Roshak AK, Capper EA, Stevenson C, Eichman C, Marshall LA. Human calciumindependent phospholipase A2 mediates lymphocyte proliferation. J Biol Chem. 2000 Nov 17;275(46):35692-8
98 Engel H, Kleespies C, Friedrich J, Breidenbach M, Kallenborn A, Schondorf T,Kolhagen H, Mallmann P. Detection of circulating tumour cells in patients with breast or ovarian cancer by molecular cytogenetics. Br J Cancer. 1999;81(7):1165-73
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75 Sompayrac L, Jane S, Burn TC, et al. Overexpression of myotonic dystrophy kinase in BC3H1 cells induces the skeletal muscle phenotype. J Bio Chem. 1996; 271(1):548-52
76 Chomezynski P,Sacchi N. Single-step method of RNA Isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal. Biochem 1987; 162:156-9.
77 Liang P, Averboukh L,Parade AB. Distribution and cloning of eukaryotic mRNAs by means of differential display: refinements and optimization. Nucleic Acids Res 1993; 21:3269-75.
78 Mager WH. Control of ribosomal protein gene expression. Biochim Biophys Acta 1988; 949(1):1-15.
79 Kenmochi N, Kawaguchi T, Rozen S, Davis E, Goodman N, Hudson TJ, Tanaka T,Page DC. A map of 75 human ribosomal protein genes. Genome Res 1998; 8(5):509-23.
80 Kondoh N, Schweinfest CW, Henderson KW,Papas TS. Differential expression of S19 ribosomal protein, laminin-binding protein, and human lymphocyte antigen class I messenger RNAs associated with colon carcinoma progression and differentiation.Cancer Res 1992; 52(4):791-6.
81 Suzuki K, Olvera J,Wool IG. The primary structure of rat ribosomal protein S19.Biochimie 1990; 72(4):299-302.
82 Shim C, Zhang W, Rhee CH,Lee JH. Profiling of differentially expressed genes in human primary cervical cancer by complementary DNA expression array. Clin.Cancer Res 1998; 4(12):3045-50.
83 Rhodes LD,Van-Beneden RJ. Isolation of the cDNA and characterization of mRNA expression of ribosomal protein S19 from the soft-shell clam, Mya arenaria. Gene 1997; 197(1-2):295-304.
84 Kenmochi N, Kawaguchi T, Rozen S, Davis E, Goodman N, Hudson TJ, Tanaka T,Page DC. A map of 75 human ribosomal protein genes. Genome Res 1998; 8:509- 23.
85 Nishiura H, Tanase S, Sibuya Y, Nishimura T,Yamamoto T. Determination of the cross-linked residues in homo-dimerization of S19 ribosomal protein concomitant with exhibition of monocyte chemotactic activity. Lab. Invest 1999; 79(8):915-23.
86 Shrestha A, Horino K, Nishiura H,Yamamoto T. cquired immune response as a consequence of the macrophage-dependent apoptotic cell clearance and role of the monocyte chemotactic S19 ribosomal protein dimer in this connection. Lab. Invest1999; 79(12):1629-42.
87 Willig TN, Draptchinskaia N, Dianzani I, Ball S, Niemeyer C, Ramenghi U, Orfali K, Gustavsson P, Garelli E, Brusco A, Tiemann C, Perignon JL, Bouchier C, Cicchiello L, Dahl N, Mohandas N,Tchernia G. Mutations in ribosomal protein S19 gene and diamond blackfan anemia: wide variations in phenotypic expression. Blood 1999; 94(12):4294-306.
88 Diatchenko L, Lau YF, Campbell AP, Chenchik A, Moqadam F, Huang B,Lukyanov S, Lukyanov K, Gurskaya N, Sverdlov ED, Siebert PD. Suppression subtractive hybridization: a method for generating differentially regulated or tissuespecific cDNA probes and libraries. Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):6025-30
89 Simons M, Wang M, McBride OW, Kawamoto S, Yamakawa K, Gdula D,Adelstein RS, Weir L. Human nonmuscle myosin heavy chains are encoded by two genes located on different chromosomes. Circ Res. 1991 Aug;69(2):530-9
90 Yang DC, Wang F, Elliott RL, Head JF. Expression of transferrin receptor and ferritin H-chain mRNA are associated with clinical and histopathological prognostic indicators in breast cancer. Anticancer Res. 2001 Jan-Feb;21(1B):541-9
91 Woodman P. Vesicle transport: more work for the Rabs? Curr Biol. 1998 Mar12;8(6):R199-201. Review
92 Gerdes HH, Rosa P, Phillips E, Baeuerle PA, Frank R, Argos P, Huttner WB. The primary structure of human secretogranin II, a widespread tyrosine-sulfated secretory granule protein that exhibits low pH- and calcium-induced aggregation. J Biol Chem 1989 Jul 15;264(20):12009-12015
93 Leitner B, Schneitler C, Klocker H, Volknandt W, Zimmermann H, Winkler H,Fischer-Colbrie R. Formation and sequence analysis of secretoneurin, a neuropeptide derived from secretogranin II, in mammalian, bird, reptile, amphibian and fish brains. Neurosci Lett 1998 May 29;248(2):105-108
94 kobayashi S, Kohda T, Miyoshi N, Kuroiwa Y, Aisaka K, Tsutsumi O, Kaneko-Ishino T, Ishino F. Human PEG1/MEST, an imprinted gene on chromosome 7. Hum. Mol. Genet 1997;6:781-6
95 Pedersen IS, Dervan PA, Broderick D, Harrison M, Miller N, Delany E, O'Shea D,Costello P, McGoldrick A, Keating G, Tobin B, Gorey T, McCann A. Frequent loss of imprinting of PEG1/MEST in invasive breast cancer. Cancer Res 1999 Nov 1;59(21):5449-5451
96 Billin AN, Eilers AL, Queva C, Ayer DE. Mlx, a novel Max-like BHLHZip protein that interacts with the Max network of transcription factors. J Biol Chem 1999 Dec 17;274(51):36344-36350
97 Roshak AK, Capper EA, Stevenson C, Eichman C, Marshall LA. Human calciumindependent phospholipase A2 mediates lymphocyte proliferation. J Biol Chem. 2000 Nov 17;275(46):35692-8
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