Impaired CK1 delta activity attenuates SV40-induced cellular transformation in vitro and mouse mammary carcinogenesis in vivo.
Impaired CK1 delta activity attenuates SV40-induced cellular transformation in vitro and mouse mammary carcinogenesis in vivo.
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CK1 Delta活性受损会减弱体内SV40诱导的细胞转化和小鼠乳腺癌发生。
DOI：
10.1371/journal.pone.0029709
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Knippschild U
中科院分区：
文献类型：
--
作者：
Hirner H;Günes C;Bischof J;Wolff S;Grothey A;Kühl M;Oswald F;Wegwitz F;Bösl MR;Trauzold A;Henne-Bruns D;Peifer C;Leithäuser F;Deppert W;Knippschild U
猴病毒40（SV 40）是研究体外细胞转化以及体内肿瘤发生和进展的有力工具。各种细胞激酶，其中包括CK 1家族的成员，在调节SV 40的转化活性中起重要作用，包括SV 40的主要转化蛋白T-Ag本身的转化活性。在此，我们表征了激酶活性受损的突变CK 1 δ变体对体外SV 40诱导的细胞转化的影响，以及在转基因/双转基因小鼠模型中对体内SV 40诱导的乳腺癌发生的影响。在体外激酶测定中，与wtCK 1 δ相比，CK 1 δ突变体表现出降低的激酶活性。分子模拟研究表明，位于底物结合区的突变N172 D是mutCK 1 δ活性受损的主要原因。当在最大转化SV-52细胞中稳定过表达时，CK 1 δ突变体通过显性负干扰内源性wtCK 1 δ诱导回复到最小转化表型。为了研究CK 1 δ在SV 40诱导的乳腺癌发生中的作用，我们建立了在乳清酸性蛋白（WAP）基因启动子控制下表达突变CK 1 δ的转基因小鼠，并将其与SV 40转基因WAP-T-抗原（WAP-T）小鼠杂交。WAP-T小鼠以及WAP-mutCK 1 δ/WAP-T双转基因小鼠均发生乳腺癌。而WAP-mutCK 1 δ/WAP-T双转基因动物的肿瘤发生率较低，寿命显著延长。CK 1 δ活性的降低并不影响肿瘤发生过程中的早期病变形成，这表明CK 1 δ活性受损降低了原位癌向浸润性癌生长的可能性。SV 40在WAP-T和WAP-mutCK 1 δ/WAP-T肿瘤中的不同致瘤潜力也反映在已知参与肿瘤进展的各种基因的显著不同表达上，特别是那些参与wnt信号传导和DNA修复的基因。我们的数据表明，CK 1 δ失活突变损害SV 40诱导的体外细胞转化和小鼠乳腺癌的体内发生。
Simian virus 40 (SV40) is a powerful tool to study cellular transformation in vitro, as well as tumor development and progression in vivo. Various cellular kinases, among them members of the CK1 family, play an important role in modulating the transforming activity of SV40, including the transforming activity of T-Ag, the major transforming protein of SV40, itself. Here we characterized the effects of mutant CK1δ variants with impaired kinase activity on SV40-induced cell transformation in vitro, and on SV40-induced mammary carcinogenesis in vivo in a transgenic/bi-transgenic mouse model. CK1δ mutants exhibited a reduced kinase activity compared to wtCK1δ in in vitro kinase assays. Molecular modeling studies suggested that mutation N172D, located within the substrate binding region, is mainly responsible for impaired mutCK1δ activity. When stably over-expressed in maximal transformed SV-52 cells, CK1δ mutants induced reversion to a minimal transformed phenotype by dominant-negative interference with endogenous wtCK1δ. To characterize the effects of CK1δ on SV40-induced mammary carcinogenesis, we generated transgenic mice expressing mutant CK1δ under the control of the whey acidic protein (WAP) gene promoter, and crossed them with SV40 transgenic WAP-T-antigen (WAP-T) mice. Both WAP-T mice as well as WAP-mutCK1δ/WAP-T bi-transgenic mice developed breast cancer. However, tumor incidence was lower and life span was significantly longer in WAP-mutCK1δ/WAP-T bi-transgenic animals. The reduced CK1δ activity did not affect early lesion formation during tumorigenesis, suggesting that impaired CK1δ activity reduces the probability for outgrowth of in situ carcinomas to invasive carcinomas. The different tumorigenic potential of SV40 in WAP-T and WAP-mutCK1δ/WAP-T tumors was also reflected by a significantly different expression of various genes known to be involved in tumor progression, specifically of those involved in wnt-signaling and DNA repair. Our data show that inactivating mutations in CK1δ impair SV40-induced cellular transformation in vitro and mouse mammary carcinogenesis in vivo.
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跨平台表达分析表明，SV40小肿瘤抗原激活了人类细胞中的缺口，刺猬和Wnt信号。
影响因子：
3.8
作者：
Ali-Seyed, M;Laycock, N;Karanam, S;Xiao, WM;Blair, ET;Moreno, CS
通讯作者：
Moreno, CS
DOI：
10.1023/b:jomg.0000037157.94207.33
发表时间：
2004-04-01
影响因子：
2.5
作者：
Brennan, KR;Brown, AMC
通讯作者：
Brown, AMC
影响因子：
8
作者：
Alsheich-Bartok, O.;Haupt, S.;Haupt, Y.
通讯作者：
Haupt, Y.
影响因子：
5.4
作者：
BAUER, M;GUHL, E;GRAESSMANN, A
通讯作者：
GRAESSMANN, A
影响因子：
6
作者：
Frierson, HF;Ei-Naggar, AK;Hampton, GM
通讯作者：
Hampton, GM