Abstract
To identify new immortalizing genes with potential roles in tumorigenesis, we performed a genetic screen aimed to bypass the rapid and tight senescence arrest of primary fibroblasts deficient for the oncogene Bmi1. We identified the T-box member TBX2 as a potent immortalizing gene that acts by downregulating Cdkn2a (p19(ARF)). TBX2 represses the Cdkn2a (p19(ARF)) promoter and attenuates E2F1, Myc or HRAS-mediated induction of Cdkn2a (p19(ARF)). We found TBX2 to be amplified in a subset of primary human breast cancers, indicating that it might contribute to breast cancer development.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenocarcinoma / genetics*
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Adenocarcinoma / metabolism
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Animals
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Breast Neoplasms / genetics*
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Breast Neoplasms / metabolism
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COS Cells
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Carrier Proteins / genetics
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / isolation & purification
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Cell Cycle Proteins / physiology*
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Cell Transformation, Neoplastic / genetics
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Cells, Cultured
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Cellular Senescence / genetics*
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Chromosomes, Human, Pair 17 / genetics*
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Cyclin-Dependent Kinase Inhibitor p16
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DNA-Binding Proteins*
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E2F Transcription Factors
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E2F1 Transcription Factor
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Female
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Fibroblasts / cytology
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Fibroblasts / metabolism
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Gene Amplification*
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Gene Deletion
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Gene Expression Regulation, Neoplastic*
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Genes, BRCA1
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Humans
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Mice
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / isolation & purification
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Neoplasm Proteins / physiology*
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Neoplastic Syndromes, Hereditary / genetics
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Nuclear Proteins / genetics
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Oncogenes
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Polycomb Repressive Complex 1
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Promoter Regions, Genetic
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Protein Biosynthesis*
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Proteins / genetics
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins c-myc / antagonists & inhibitors
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Proto-Oncogene Proteins p21(ras) / antagonists & inhibitors
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Repressor Proteins / genetics
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Repressor Proteins / isolation & purification
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Repressor Proteins / physiology*
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Retinoblastoma-Binding Protein 1
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T-Box Domain Proteins / genetics
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T-Box Domain Proteins / isolation & purification
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T-Box Domain Proteins / physiology*
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Transcription Factor DP1
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Transcription Factors / antagonists & inhibitors
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Transfection
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Tumor Cells, Cultured
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Tumor Suppressor Protein p14ARF
Substances
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Arid4a protein, mouse
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BMI1 protein, human
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Bmi1 protein, mouse
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Carrier Proteins
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p16
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DNA-Binding Proteins
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E2F Transcription Factors
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E2F1 Transcription Factor
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E2F1 protein, human
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E2f1 protein, mouse
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Neoplasm Proteins
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Nuclear Proteins
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Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-myc
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Repressor Proteins
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Retinoblastoma-Binding Protein 1
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T-Box Domain Protein 2
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T-Box Domain Proteins
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Transcription Factor DP1
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Transcription Factors
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Tumor Suppressor Protein p14ARF
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Polycomb Repressive Complex 1
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HRAS protein, human
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Proto-Oncogene Proteins p21(ras)