Impaired CK1 delta activity attenuates SV40-induced cellular transformation in vitro and mouse mammary carcinogenesis in vivo.

Heidrun Hirner; Cagatay Günes; Joachim Bischof; Sonja Wolff; Arnhild Grothey; Marion Kühl; Franz Oswald; Florian Wegwitz; Michael R Bösl; Anna Trauzold; Doris Henne-Bruns; Christian Peifer; Frank Leithäuser; Wolfgang Deppert; Uwe Knippschild

Impaired CK1 delta activity attenuates SV40-induced cellular transformation in vitro and mouse mammary carcinogenesis in vivo.

Standard

Impaired CK1 delta activity attenuates SV40-induced cellular transformation in vitro and mouse mammary carcinogenesis in vivo. / Hirner, Heidrun; Günes, Cagatay; Bischof, Joachim; Wolff, Sonja; Grothey, Arnhild; Kühl, Marion; Oswald, Franz; Wegwitz, Florian; Bösl, Michael R; Trauzold, Anna; Henne-Bruns, Doris; Peifer, Christian; Leithäuser, Frank; Deppert, Wolfgang; Knippschild, Uwe.

in: PLOS ONE, Jahrgang 7, Nr. 1, 1, 2012, S. 29709.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

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 2012, 'Impaired CK1 delta activity attenuates SV40-induced cellular transformation in vitro and mouse mammary carcinogenesis in vivo.', PLOS ONE, Jg. 7, Nr. 1, 1, S. 29709. <http://www.ncbi.nlm.nih.gov/pubmed/22235331?dopt=Citation>

APA

Hirner, H., Günes, C., Bischof, J., Wolff, S., Grothey, A., Kühl, M., Oswald, F., Wegwitz, F., Bösl, M. R., Trauzold, A., Henne-Bruns, D., Peifer, C., Leithäuser, F., Deppert, W., & Knippschild, U. (2012). Impaired CK1 delta activity attenuates SV40-induced cellular transformation in vitro and mouse mammary carcinogenesis in vivo. PLOS ONE, 7(1), 29709. [1]. http://www.ncbi.nlm.nih.gov/pubmed/22235331?dopt=Citation

Vancouver

Hirner H, Günes C, Bischof J, Wolff S, Grothey A, Kühl M et al. Impaired CK1 delta activity attenuates SV40-induced cellular transformation in vitro and mouse mammary carcinogenesis in vivo. PLOS ONE. 2012;7(1):29709. 1.

Bibtex

@article{99db32b167404e408194681e625ed737,

title = "Impaired CK1 delta activity attenuates SV40-induced cellular transformation in vitro and mouse mammary carcinogenesis in vivo.",

abstract = "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 CK1? 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. CK1? mutants exhibited a reduced kinase activity compared to wtCK1? in in vitro kinase assays. Molecular modeling studies suggested that mutation N172D, located within the substrate binding region, is mainly responsible for impaired mutCK1? activity. When stably over-expressed in maximal transformed SV-52 cells, CK1? mutants induced reversion to a minimal transformed phenotype by dominant-negative interference with endogenous wtCK1?. To characterize the effects of CK1? on SV40-induced mammary carcinogenesis, we generated transgenic mice expressing mutant CK1? 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-mutCK1?/WAP-T bi-transgenic mice developed breast cancer. However, tumor incidence was lower and life span was significantly longer in WAP-mutCK1?/WAP-T bi-transgenic animals. The reduced CK1? activity did not affect early lesion formation during tumorigenesis, suggesting that impaired CK1? activity reduces the probability for outgrowth of in situ carcinomas to invasive carcinomas. The different tumorigenic potential of SV40 in WAP-T and WAP-mutCK1?/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 CK1? impair SV40-induced cellular transformation in vitro and mouse mammary carcinogenesis in vivo.",

keywords = "Animals, Male, Female, Survival Analysis, Disease Progression, Gene Expression Regulation, Mice, Mice, Inbred BALB C, Phenotype, Cell Line, Tumor, Models, Molecular, Protein Structure, Tertiary, Mice, Transgenic, Phosphorylation, Cell Line, *Mutation, Milk Proteins/genetics, Promoter Regions, Genetic/genetics, Antigens, Viral, Tumor/immunology, Casein Kinase Idelta/chemistry/*genetics/*metabolism, Cell Transformation, Viral/*genetics, Mammary Glands, Animal/metabolism/pathology/virology, Mammary Neoplasms, Experimental/*enzymology/genetics/*pathology/virology, Simian virus 40/immunology/*physiology, Animals, Male, Female, Survival Analysis, Disease Progression, Gene Expression Regulation, Mice, Mice, Inbred BALB C, Phenotype, Cell Line, Tumor, Models, Molecular, Protein Structure, Tertiary, Mice, Transgenic, Phosphorylation, Cell Line, *Mutation, Milk Proteins/genetics, Promoter Regions, Genetic/genetics, Antigens, Viral, Tumor/immunology, Casein Kinase Idelta/chemistry/*genetics/*metabolism, Cell Transformation, Viral/*genetics, Mammary Glands, Animal/metabolism/pathology/virology, Mammary Neoplasms, Experimental/*enzymology/genetics/*pathology/virology, Simian virus 40/immunology/*physiology",

author = "Heidrun Hirner and Cagatay G{\"u}nes and Joachim Bischof and Sonja Wolff and Arnhild Grothey and Marion K{\"u}hl and Franz Oswald and Florian Wegwitz and B{\"o}sl, {Michael R} and Anna Trauzold and Doris Henne-Bruns and Christian Peifer and Frank Leith{\"a}user and Wolfgang Deppert and Uwe Knippschild",

year = "2012",

language = "English",

volume = "7",

pages = "29709",

journal = "PLOS ONE",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "1",

}

RIS

TY - JOUR

T1 - Impaired CK1 delta activity attenuates SV40-induced cellular transformation in vitro and mouse mammary carcinogenesis in vivo.

AU - Hirner, Heidrun

AU - Günes, Cagatay

AU - Bischof, Joachim

AU - Wolff, Sonja

AU - Grothey, Arnhild

AU - Kühl, Marion

AU - Oswald, Franz

AU - Wegwitz, Florian

AU - Bösl, Michael R

AU - Trauzold, Anna

AU - Henne-Bruns, Doris

AU - Peifer, Christian

AU - Leithäuser, Frank

AU - Deppert, Wolfgang

AU - Knippschild, Uwe

PY - 2012

Y1 - 2012

N2 - 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 CK1? 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. CK1? mutants exhibited a reduced kinase activity compared to wtCK1? in in vitro kinase assays. Molecular modeling studies suggested that mutation N172D, located within the substrate binding region, is mainly responsible for impaired mutCK1? activity. When stably over-expressed in maximal transformed SV-52 cells, CK1? mutants induced reversion to a minimal transformed phenotype by dominant-negative interference with endogenous wtCK1?. To characterize the effects of CK1? on SV40-induced mammary carcinogenesis, we generated transgenic mice expressing mutant CK1? 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-mutCK1?/WAP-T bi-transgenic mice developed breast cancer. However, tumor incidence was lower and life span was significantly longer in WAP-mutCK1?/WAP-T bi-transgenic animals. The reduced CK1? activity did not affect early lesion formation during tumorigenesis, suggesting that impaired CK1? activity reduces the probability for outgrowth of in situ carcinomas to invasive carcinomas. The different tumorigenic potential of SV40 in WAP-T and WAP-mutCK1?/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 CK1? impair SV40-induced cellular transformation in vitro and mouse mammary carcinogenesis in vivo.

AB - 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 CK1? 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. CK1? mutants exhibited a reduced kinase activity compared to wtCK1? in in vitro kinase assays. Molecular modeling studies suggested that mutation N172D, located within the substrate binding region, is mainly responsible for impaired mutCK1? activity. When stably over-expressed in maximal transformed SV-52 cells, CK1? mutants induced reversion to a minimal transformed phenotype by dominant-negative interference with endogenous wtCK1?. To characterize the effects of CK1? on SV40-induced mammary carcinogenesis, we generated transgenic mice expressing mutant CK1? 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-mutCK1?/WAP-T bi-transgenic mice developed breast cancer. However, tumor incidence was lower and life span was significantly longer in WAP-mutCK1?/WAP-T bi-transgenic animals. The reduced CK1? activity did not affect early lesion formation during tumorigenesis, suggesting that impaired CK1? activity reduces the probability for outgrowth of in situ carcinomas to invasive carcinomas. The different tumorigenic potential of SV40 in WAP-T and WAP-mutCK1?/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 CK1? impair SV40-induced cellular transformation in vitro and mouse mammary carcinogenesis in vivo.

KW - Animals

KW - Male

KW - Female

KW - Survival Analysis

KW - Disease Progression

KW - Gene Expression Regulation

KW - Mice

KW - Mice, Inbred BALB C

KW - Phenotype

KW - Cell Line, Tumor

KW - Models, Molecular

KW - Protein Structure, Tertiary

KW - Mice, Transgenic

KW - Phosphorylation

KW - Cell Line

KW - Mutation

KW - Milk Proteins/genetics

KW - Promoter Regions, Genetic/genetics

KW - Antigens, Viral, Tumor/immunology

KW - Casein Kinase Idelta/chemistry/genetics/metabolism

KW - Cell Transformation, Viral/genetics

KW - Mammary Glands, Animal/metabolism/pathology/virology

KW - Mammary Neoplasms, Experimental/enzymology/genetics/pathology/virology

KW - Simian virus 40/immunology/physiology