CEBP factors regulate telomerase reverse transcriptase promoter activity in whey acidic protein-T mice during mammary carcinogenesis
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CEBP factors regulate telomerase reverse transcriptase promoter activity in whey acidic protein-T mice during mammary carcinogenesis. / Kumar, Mukesh; Witt, Britta; Knippschild, Uwe; Koch, Sylvia; Meena, Jitendra K; Heinlein, Christina; Weise, Julia M; Krepulat, Frauke; Kuchenbauer, Florian; Iben, Sebastian; Rudolph, Karl-Lenhard; Deppert, Wolfgang; Günes, Cagatay.
in: INT J CANCER, Jahrgang 132, Nr. 9, 9, 01.05.2013, S. 2032-2043.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - CEBP factors regulate telomerase reverse transcriptase promoter activity in whey acidic protein-T mice during mammary carcinogenesis
AU - Kumar, Mukesh
AU - Witt, Britta
AU - Knippschild, Uwe
AU - Koch, Sylvia
AU - Meena, Jitendra K
AU - Heinlein, Christina
AU - Weise, Julia M
AU - Krepulat, Frauke
AU - Kuchenbauer, Florian
AU - Iben, Sebastian
AU - Rudolph, Karl-Lenhard
AU - Deppert, Wolfgang
AU - Günes, Cagatay
N1 - Copyright © 2012 UICC.
PY - 2013/5/1
Y1 - 2013/5/1
N2 - Telomerase is activated in the majority of invasive breast cancers, but the time point of telomerase activation during mammary carcinogenesis is not clear. We have recently presented a transgenic mouse model to study human telomerase reverse transcriptase (TERT) gene expression in vivo (hTERTp-lacZ). In the present study, hTERTp-lacZxWAP-T bitransgenic mice were generated to analyze the mechanisms responsible for human and mouse TERT upregulation during tumor progression in vivo. We found that telomerase activity and TERT expression were consistently upregulated in SV40-induced invasive mammary tumors compared to normal and hyperplastic tissues and ductal carcinoma in situ (DCIS). Human and mouse TERT genes are regulated similarly in the breast tissue, involving the CEBP transcription factors. Loss of CEBP-? and induction of CEBP-? expression correlated well with the activation of TERT expression in mouse mammary tumors. Transfection of CEBP-? into human or murine cells resulted in TERT repression, whereas knockdown of CEBP-? in primary human mammary epithelial cells resulted in reactivation of endogenous TERT expression and telomerase activity. Conversely, ectopic expression of CEBP-? activated endogenous TERT gene expression. Moreover, ChIP and EMSA experiments revealed binding of CEBP-? and CEBP-? to human TERT-promoter. This is the first evidence indicating that CEBP-? and CEBP-? are involved in TERT gene regulation during carcinogenesis.
AB - Telomerase is activated in the majority of invasive breast cancers, but the time point of telomerase activation during mammary carcinogenesis is not clear. We have recently presented a transgenic mouse model to study human telomerase reverse transcriptase (TERT) gene expression in vivo (hTERTp-lacZ). In the present study, hTERTp-lacZxWAP-T bitransgenic mice were generated to analyze the mechanisms responsible for human and mouse TERT upregulation during tumor progression in vivo. We found that telomerase activity and TERT expression were consistently upregulated in SV40-induced invasive mammary tumors compared to normal and hyperplastic tissues and ductal carcinoma in situ (DCIS). Human and mouse TERT genes are regulated similarly in the breast tissue, involving the CEBP transcription factors. Loss of CEBP-? and induction of CEBP-? expression correlated well with the activation of TERT expression in mouse mammary tumors. Transfection of CEBP-? into human or murine cells resulted in TERT repression, whereas knockdown of CEBP-? in primary human mammary epithelial cells resulted in reactivation of endogenous TERT expression and telomerase activity. Conversely, ectopic expression of CEBP-? activated endogenous TERT gene expression. Moreover, ChIP and EMSA experiments revealed binding of CEBP-? and CEBP-? to human TERT-promoter. This is the first evidence indicating that CEBP-? and CEBP-? are involved in TERT gene regulation during carcinogenesis.
KW - Animals
KW - Humans
KW - Female
KW - Mice
KW - Mice, Inbred BALB C
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Gene Expression Regulation, Neoplastic
KW - Mice, Transgenic
KW - Blotting, Western
KW - Tumor Cells, Cultured
KW - Chromatin Immunoprecipitation
KW - Immunoenzyme Techniques
KW - Promoter Regions, Genetic/genetics
KW - Real-Time Polymerase Chain Reaction
KW - Transcriptional Activation
KW - Telomerase/genetics/metabolism
KW - RNA, Messenger/genetics
KW - Cell Transformation, Neoplastic/pathology
KW - Milk Proteins/genetics
KW - CCAAT-Enhancer-Binding Proteins/genetics/metabolism
KW - Electrophoretic Mobility Shift Assay
KW - Luciferases/metabolism
KW - Mammary Neoplasms, Experimental/genetics/metabolism/pathology
KW - Animals
KW - Humans
KW - Female
KW - Mice
KW - Mice, Inbred BALB C
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Gene Expression Regulation, Neoplastic
KW - Mice, Transgenic
KW - Blotting, Western
KW - Tumor Cells, Cultured
KW - Chromatin Immunoprecipitation
KW - Immunoenzyme Techniques
KW - Promoter Regions, Genetic/genetics
KW - Real-Time Polymerase Chain Reaction
KW - Transcriptional Activation
KW - Telomerase/genetics/metabolism
KW - RNA, Messenger/genetics
KW - Cell Transformation, Neoplastic/pathology
KW - Milk Proteins/genetics
KW - CCAAT-Enhancer-Binding Proteins/genetics/metabolism
KW - Electrophoretic Mobility Shift Assay
KW - Luciferases/metabolism
KW - Mammary Neoplasms, Experimental/genetics/metabolism/pathology
U2 - 10.1002/ijc.27880
DO - 10.1002/ijc.27880
M3 - SCORING: Journal article
C2 - 23023397
VL - 132
SP - 2032
EP - 2043
JO - INT J CANCER
JF - INT J CANCER
SN - 0020-7136
IS - 9
M1 - 9
ER -
