Senescence bypass screen identifies TBX2, which represses Cdkn2a (p19(ARF)) and is amplified in a subset of human breast cancers.
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.
Jacobs
J J
JJ
Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Keblusek
P
P
Robanus-Maandag
E
E
Kristel
P
P
Lingbeek
M
M
Nederlof
P M
PM
van Welsem
T
T
van de Vijver
M J
MJ
Koh
E Y
EY
Daley
G Q
GQ
van Lohuizen
M
M
D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics*; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005784:Gene Amplification; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D009857:Oncogenes; D063150:Polycomb Repressive Complex 1; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors; D012097:Repressor Proteins / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D056465:Retinoblastoma-Binding Protein 1; D020825:T-Box Domain Proteins / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D014162:Transfection; D014407:Tumor Cells, Cultured; D025803:Tumor Suppressor Protein p14ARF
C533431:Arid4a protein, mouse; C069077:BMI1 protein, human; C489421:Bmi1 protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C493754:E2f1 protein, mouse; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; D056465:Retinoblastoma-Binding Protein 1; C097348:T-Box Domain Protein 2; D020825:T-Box Domain Proteins; D050680:Transcription Factor DP1; D014157:Transcription Factors; D025803:Tumor Suppressor Protein p14ARF; D063150:Polycomb Repressive Complex 1; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)