Senescence bypass screen identifies TBX2, which represses Cdkn2a (p19ARF) 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 (p19ARF). TBX2 represses the Cdkn2a (p19ARF) promoter and attenuates E2F1, Myc or HRAS-mediated induction of Cdkn2a (p19ARF). We found TBX2 to be amplified in a subset of primary human breast cancers, indicating that it might contribute to breast cancer development.

[1]  L. Chin,et al.  Role of the INK4a Locus in Tumor Suppression and Cell Mortality , 1996, Cell.

[2]  Mark J Alkema,et al.  Perturbation of B and T cell development and predisposition to lymphomagenesis in EμBmi1 transgenic mice require the Bmi1 RING finger , 1997, Oncogene.

[3]  Randall T Moon,et al.  Mechanism and function of signal transduction by the Wnt/β-catenin and Wnt/Ca2+ pathways , 1999, Oncogene.

[4]  G. Peters,et al.  The p16INK4a/CDKN2A tumor suppressor and its relatives. , 1998, Biochimica et biophysica acta.

[5]  Richard A. Ashmun,et al.  Tumor Suppression at the Mouse INK4a Locus Mediated by the Alternative Reading Frame Product p19 ARF , 1997, Cell.

[6]  F. Zindy,et al.  Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[7]  Anton Berns,et al.  Identification of cooperating oncogenes in Eμ-myc transgenic mice by provirus tagging , 1991, Cell.

[8]  R. DePinho,et al.  The INK4A/ARF locus and its two gene products. , 1999, Current opinion in genetics & development.

[9]  Harold E. Varmus,et al.  Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome , 1982, Cell.

[10]  L. Silver,et al.  The T‐box gene family , 1998, BioEssays : news and reviews in molecular, cellular and developmental biology.

[11]  C. Wicking,et al.  The hedgehog signalling pathway in tumorigenesis and development , 1999, Oncogene.

[12]  Charles J. Sherr,et al.  Nucleolar Arf sequesters Mdm2 and activates p53 , 1999, Nature Cell Biology.

[13]  Y. Rao,et al.  Transcription repression by Xenopus ET and its human ortholog TBX3, a gene involved in ulnar-mammary syndrome. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[14]  Y. Xiong,et al.  Mutations in human ARF exon 2 disrupt its nucleolar localization and impair its ability to block nuclear export of MDM2 and p53. , 1999, Molecular cell.

[15]  O. Kallioniemi,et al.  Increased copy number at 17q22‐q24 by CGH in breast cancer is due to high‐level amplification of two separate regions , 1997, Genes, chromosomes & cancer.

[16]  C. R. Goding,et al.  Brachyury-Related Transcription Factor Tbx2 and Repression of the Melanocyte-Specific TRP-1 Promoter , 1998, Molecular and Cellular Biology.

[17]  K Kornfeld,et al.  Multiple docking sites on substrate proteins form a modular system that mediates recognition by ERK MAP kinase. , 1999, Genes & development.

[18]  R. DePinho,et al.  The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus , 1999, Nature.

[19]  B. Beatty,et al.  Cloning and mapping of a human gene (TBX2) sharing a highly conserved protein motif with the Drosophila omb gene. , 1995, Genomics.

[20]  A. Sparks,et al.  Identification of c-MYC as a target of the APC pathway. , 1998, Science.

[21]  L. Silver,et al.  Involvement of T-box genes Tbx2-Tbx5 in vertebrate limb specification and development. , 1998, Development.

[22]  C. Sherr,et al.  Tumor surveillance via the ARF-p53 pathway. , 1998, Genes & development.

[23]  J. D. Weber,et al.  The ARF/p53 pathway. , 2000, Current opinion in genetics & development.

[24]  F. Hecht,et al.  Ring 22 chromosomes in dermatofibrosarcoma protuberans are low-level amplifiers of chromosome 17 and 22 sequences. , 1995, Cancer research.

[25]  M. Roussel,et al.  Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis. , 1999, Genes & development.

[26]  G. Hannon,et al.  A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4 , 1993, Nature.

[27]  Peter A. Jones,et al.  The Human ARF Cell Cycle Regulatory Gene Promoter Is a CpG Island Which Can Be Silenced by DNA Methylation and Down-Regulated by Wild-Type p53 , 1998, Molecular and Cellular Biology.

[28]  Y. Haupt,et al.  bmi-1 transgene induces lymphomas and collaborates with myc in tumorigenesis. , 1993, Oncogene.

[29]  Yue Xiong,et al.  ARF Promotes MDM2 Degradation and Stabilizes p53: ARF-INK4a Locus Deletion Impairs Both the Rb and p53 Tumor Suppression Pathways , 1998, Cell.

[30]  S. Culine,et al.  Relating genotype and phenotype in breast cancer: an analysis of the prognostic significance of amplification at eight different genes or loci and of p53 mutations. , 2000, Cancer research.

[31]  G. Prendergast,et al.  c‐Myc represses transcription in vivo by a novel mechanism dependent on the initiator element and Myc box II. , 1994, The EMBO journal.

[32]  F. Couch,et al.  Localization of PS6K to chromosomal region 17q23 and determination of its amplification in breast cancer. , 1999, Cancer research.

[33]  H. Clevers,et al.  Synergy between tumor suppressor APC and the beta-catenin-Tcf4 target Tcf1. , 1999, Science.

[34]  A. Levine,et al.  P19(ARF) stabilizes p53 by blocking nucleo-cytoplasmic shuttling of Mdm2. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[35]  A. Levine.  p53, the Cellular Gatekeeper for Growth and Division , 1997, Cell.

[36]  C. Theillet,et al.  Comparative genomic hybridization analysis of breast tumors with predetermined profiles of DNA amplification. , 1997, Cancer research.

[37]  Karen H. Vousden,et al.  p14ARF links the tumour suppressors RB and p53 , 1998, Nature.

[38]  M. Wolter,et al.  Analysis of genomic alterations in benign, atypical, and anaplastic meningiomas: toward a genetic model of meningioma progression. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[39]  L. Kedes,et al.  Twist is a potential oncogene that inhibits apoptosis. , 1999, Genes & development.

[40]  Kevin Ryan,et al.  The alternative product from the human CDKN2A locus, p14ARF, participates in a regulatory feedback loop with p53 and MDM2 , 1998, The EMBO journal.

[41]  F. Zindy,et al.  Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest , 1995, Cell.

[42]  Cellular senescence and cancer , 1999, The Journal of pathology.

[43]  G. Hannon,et al.  Cloning and characterization of murine p16INK4a and p15INK4b genes. , 1995, Oncogene.

[44]  Ken Chen,et al.  The Ink4a Tumor Suppressor Gene Product, p19Arf, Interacts with MDM2 and Neutralizes MDM2's Inhibition of p53 , 1998, Cell.

[45]  J L Cleveland,et al.  Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. , 1998, Genes & development.

[46]  T. Taniguchi,et al.  Cellular commitment to oncogene-induced transformation or apoptosis is dependent on the transcription factor IRF-1 , 1994, Cell.

[47]  M. J. van de Vijver,et al.  p53 protein accumulation and response to adjuvant chemotherapy in premenopausal women with node-negative early breast cancer. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[48]  M. Roussel,et al.  Induction of ARF tumor suppressor gene expression and cell cycle arrest by transcription factor DMP1. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[49]  S. Lowe,et al.  INK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance by disabling p53. , 1999, Genes & development.