Senescence bypass screen identifies TBX2, which represses Cdkn2a (p19(ARF)) and is amplified in a subset of human breast cancers

Nat Genet. 2000 Nov;26(3):291-9. doi: 10.1038/81583.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenocarcinoma / genetics*
  • Adenocarcinoma / metabolism
  • Animals
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • COS Cells
  • Carrier Proteins / genetics
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / isolation & purification
  • Cell Cycle Proteins / physiology*
  • Cell Transformation, Neoplastic / genetics
  • Cells, Cultured
  • Cellular Senescence / genetics*
  • Chromosomes, Human, Pair 17 / genetics*
  • Cyclin-Dependent Kinase Inhibitor p16
  • DNA-Binding Proteins*
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Gene Amplification*
  • Gene Deletion
  • Gene Expression Regulation, Neoplastic*
  • Genes, BRCA1
  • Humans
  • Mice
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / isolation & purification
  • Neoplasm Proteins / physiology*
  • Neoplastic Syndromes, Hereditary / genetics
  • Nuclear Proteins / genetics
  • Oncogenes
  • Polycomb Repressive Complex 1
  • Promoter Regions, Genetic
  • Protein Biosynthesis*
  • Proteins / genetics
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins c-myc / antagonists & inhibitors
  • Proto-Oncogene Proteins p21(ras) / antagonists & inhibitors
  • Repressor Proteins / genetics
  • Repressor Proteins / isolation & purification
  • Repressor Proteins / physiology*
  • Retinoblastoma-Binding Protein 1
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / isolation & purification
  • T-Box Domain Proteins / physiology*
  • Transcription Factor DP1
  • Transcription Factors / antagonists & inhibitors
  • Transfection
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p14ARF

Substances

  • Arid4a protein, mouse
  • BMI1 protein, human
  • Bmi1 protein, mouse
  • Carrier Proteins
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p16
  • DNA-Binding Proteins
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • E2f1 protein, mouse
  • Neoplasm Proteins
  • Nuclear Proteins
  • Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-myc
  • Repressor Proteins
  • Retinoblastoma-Binding Protein 1
  • T-Box Domain Protein 2
  • T-Box Domain Proteins
  • Transcription Factor DP1
  • Transcription Factors
  • Tumor Suppressor Protein p14ARF
  • Polycomb Repressive Complex 1
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)