Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Gene amplification and associated loss of 5′ regulatory sequences of CoAA in human cancers

Oncogene volume 26, pages 822–835 (2007)Cite this article

Abstract

CoAA is an RRM-containing transcriptional coactivator that stimulates transcriptional activation and regulates alternative splicing. We show that the CoAA gene is amplified at the chromosome 11q13 locus in a subset of primary human cancers including non-small cell lung carcinoma, squamous cell skin carcinoma and lymphoma. Analysis of 42 primary tumors suggests that CoAA amplifies independently from the CCND1 locus. Detailed mapping of three CoAA amplicons reveals that the amplified CoAA gene is consistently located at the 5′ boundaries of the amplicons. The CoAA coding and basal promoter sequences are retained within the amplicons but upstream silencing sequences are lost. CoAA protein is overexpressed in tumors containing the amplified CoAA gene. RNA dot blot analysis of 100 cases of primary tumors suggests elevated CoAA mRNA expression. CoAA positively regulates its own basal promoter in transfection assays. Thus, gene amplification, loss of silencing sequence and positive feedback regulation may lead to drastic upregulation of CoAA protein. CoAA has transforming activities when tested in soft agar assays, and CoAA is homologous to oncoproteins EWS and TLS, which regulate alternative splicing. These data imply that CoAA may share a similar oncogenic mechanism with oncogene EWS and that CoAA deregulation may alter the alternative splicing of target genes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  • Antonson P, Schuster GU, Wang L, Rozell B, Holter E, Flodby P et al. (2003). Inactivation of the nuclear receptor coactivator RAP250 in mice results in placental vascular dysfunction. Mol Cell Biol 23: 1260–1268.

    Article  CAS  Google Scholar 

  • Anzick SL, Kononen J, Walker RL, Azorsa DO, Tanner MM, Guan XY et al. (1997). AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science 277: 965–968.

    Article  CAS  Google Scholar 

  • Aranda A, Pascual A . (2001). Nuclear hormone receptors and gene expression. Physiol Rev 81: 1269–1304.

    Article  CAS  Google Scholar 

  • Auboeuf D, Dowhan DH, Dutertre M, Martin N, Berget SM, O'Malley BW . (2005). A subset of nuclear receptor coregulators act as coupling proteins during synthesis and maturation of RNA transcripts. Mol Cell Biol 25: 5307–5316.

    Article  CAS  Google Scholar 

  • Auboeuf D, Dowhan DH, Li X, Larkin K, Ko L, Berget SM et al. (2004). CoAA, a nuclear receptor coactivator protein at the interface of transcriptional coactivation and RNA splicing. Mol Cell Biol 24: 442–453.

    Article  CAS  Google Scholar 

  • Auboeuf D, Honig A, Berget SM, O'Malley BW . (2002). Coordinate regulation of transcription and splicing by steroid receptor coregulators. Science 298: 416–419.

    Article  CAS  Google Scholar 

  • Brett D, Whitehouse S, Antonson P, Shipley J, Cooper C, Goodwin G . (1997). The SYT protein involved in the t(X;18) synovial sarcoma translocation is a transcriptional activator localised in nuclear bodies. Hum Mol Genet 6: 1559–1564.

    Article  CAS  Google Scholar 

  • Buttel I, Fechter A, Schwab M . (2004). Common fragile sites and cancer: targeted cloning by insertional mutagenesis. Ann NY Acad Sci 1028: 14–27.

    PubMed  Google Scholar 

  • Bystritskiy AA, Razin SV . (2004). Breakpoint clusters: reason or consequence? Crit Rev Eukaryot Gene Expr 14: 65–77.

    Article  CAS  Google Scholar 

  • Caiafa P, Zampieri M . (2005). DNA methylation and chromatin structure: the puzzling CpG islands. J Cell Biochem 94: 257–265.

    Article  CAS  Google Scholar 

  • Clark J, Rocques PJ, Crew AJ, Gill S, Shipley J, Chan AM et al. (1994). Identification of novel genes, SYT and SSX, involved in the t(X;18)(p11.2;q11.2) translocation found in human synovial sarcoma. Nat Genet 7: 502–508.

    Article  CAS  Google Scholar 

  • Coquelle A, Pipiras E, Toledo F, Buttin G, Debatisse M . (1997). Expression of fragile sites triggers intrachromosomal mammalian gene amplification and sets boundaries to early amplicons. Cell 89: 215–225.

    Article  CAS  Google Scholar 

  • Das PM, Singal R . (2004). DNA methylation and cancer. J Clin Oncol 22: 4632–4642.

    Article  CAS  Google Scholar 

  • Fox AH, Lam YW, Leung AK, Lyon CE, Andersen J, Mann M et al. (2002). Paraspeckles: a novel nuclear domain. Curr Biol 12: 13–25.

    Article  CAS  Google Scholar 

  • Gibbons R, Dugaiczyk A . (2005). Phylogenetic roots of Alu-mediated rearrangements leading to cancer. Genome 48: 160–167.

    Article  CAS  Google Scholar 

  • Grandinetti KB, Spengler BA, Biedler JL, Ross RA . (2006). Loss of one HuD allele on chromosome #1p selects for amplification of the N-myc proto-oncogene in human neuroblastoma cells. Oncogene 25: 706–712.

    Article  CAS  Google Scholar 

  • Greaves MF, Wiemels J . (2003). Origins of chromosome translocations in childhood leukaemia. Nat Rev Cancer 3: 639–649.

    Article  CAS  Google Scholar 

  • Guan XY, Xu J, Anzick SL, Zhang H, Trent JM, Meltzer PS . (1996). Hybrid selection of transcribed sequences from microdissected DNA: isolation of genes within amplified region at 20q11-q13.2 in breast cancer. Cancer Res 56: 3446–3450.

    CAS  PubMed  Google Scholar 

  • Iwasaki T, Chin WW, Ko L . (2001). Identification and characterization of RRM-containing coactivator activator (CoAA) as TRBP-interacting protein, and its splice variant as a coactivator modulator (CoAM). J Biol Chem 276: 33375–33383.

    Article  CAS  Google Scholar 

  • Jasinska A, Krzyzosiak WJ . (2004). Repetitive sequences that shape the human transcriptome. FEBS Lett 567: 136–141.

    Article  CAS  Google Scholar 

  • Kalnina Z, Zayakin P, Silina K, Line A . (2005). Alterations of pre-mRNA splicing in cancer. Genes Chromosomes Cancer 42: 342–357.

    Article  CAS  Google Scholar 

  • Kim CF, Jackson EL, Woolfenden AE, Lawrence S, Babar I, Vogel S et al. (2005). Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121: 823–835.

    Article  CAS  Google Scholar 

  • Kim J, Pelletier J . (1999). Molecular genetics of chromosome translocations involving EWS and related family members. Physiol Genom. 1: 127–138.

    Article  CAS  Google Scholar 

  • Ko L, Cardona GR, Chin WW . (2000). Thyroid hormone receptor-binding protein, an LXXLL motif-containing protein, functions as a general coactivator. Proc Natl Acad Sci USA 97: 6212–6217.

    Article  CAS  Google Scholar 

  • Koreth J, Bakkenist CJ, McGee JO . (1999). Chromosomes, 11Q and cancer: a review. J Pathol 187: 28–38.

    Article  CAS  Google Scholar 

  • Kuang SQ, Liao L, Zhang H, Pereira FA, Yuan Y, DeMayo FJ et al. (2002). Deletion of the cancer-amplified coactivator AIB3 results in defective placentation and embryonic lethality. J Biol Chem 277: 45356–45360.

    Article  CAS  Google Scholar 

  • Lammie GA, Peters G . (1991). Chromosome 11q13 abnormalities in human cancer. Cancer Cells 3: 413–420.

    CAS  PubMed  Google Scholar 

  • Lee J, Rhee BK, Bae GY, Han YM, Kim J . (2005). Stimulation of Oct-4 activity by Ewing's sarcoma protein. Stem Cells 23: 738–751.

    Article  CAS  Google Scholar 

  • McKenna NJ, O'Malley BW . (2002). Combinatorial control of gene expression by nuclear receptors and coregulators. Cell 108: 465–474.

    Article  CAS  Google Scholar 

  • Penalva LO, Sanchez L . (2003). RNA binding protein sex-lethal (Sxl) and control of Drosophila sex determination and dosage compensation. Microbiol Mol Biol Rev 67: 343–359, table of contents.

    Article  CAS  Google Scholar 

  • Rabbitts TH . (1994). Chromosomal translocations in human cancer. Nature 372: 143–149.

    Article  CAS  Google Scholar 

  • Rabbitts TH . (1999). Perspective: chromosomal translocations can affect genes controlling gene expression and differentiation – why are these functions targeted? J Pathol 187: 39–42.

    Article  CAS  Google Scholar 

  • Schmid CW . (1998). Does SINE evolution preclude Alu function? Nucleic Acids Res 26: 4541–4550.

    Article  CAS  Google Scholar 

  • Smith CW, Patton JG, Nadal-Ginard B . (1989). Alternative splicing in the control of gene expression. Annu Rev Genet 23: 527–577.

    Article  CAS  Google Scholar 

  • Sorensen PH, Triche TJ . (1996). Gene fusions encoding chimaeric transcription factors in solid tumours. Semin Cancer Biol 7: 3–14.

    Article  CAS  Google Scholar 

  • Torres-Arzayus MI, Font de Mora J, Yuan J, Vazquez F, Bronson R, Rue M et al. (2004). High tumor incidence and activation of the PI3K/AKT pathway in transgenic mice define AIB1 as an oncogene. Cancer Cell 6: 263–274.

    Article  CAS  Google Scholar 

  • Yang L, Chansky HA, Hickstein DD . (2000). EWS.Fli-1 fusion protein interacts with hyperphosphorylated RNA polymerase II and interferes with serine-arginine protein-mediated RNA splicing. J Biol Chem 275: 37612–37618.

    Article  CAS  Google Scholar 

  • Yang XJ . (2004). The diverse superfamily of lysine acetyltransferases and their roles in leukemia and other diseases. Nucleic Acids Res 32: 959–976.

    Article  CAS  Google Scholar 

  • Zainabadi K, Benyamini P, Chakrabarti R, Veena MS, Chandrasekharappa SC, Gatti RA et al. (2005). A 700-kb physical and transcription map of the cervical cancer tumor suppressor gene locus on chromosome 11q13. Genomics 85: 704–714.

    Article  CAS  Google Scholar 

  • Zinszner H, Albalat R, Ron D . (1994). A novel effector domain from the RNA-binding protein TLS or EWS is required for oncogenic transformation by CHOP. Genes Dev 8: 2513–2526.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported, in part, by the Georgia Cancer Coalition (L Ko). We thank Paul S Meltzer at National Institutes of Health for discussion of the manuscript. We thank Liu Yang at University of Washington for the EWS-Fli plasmids, and Ning Zhu at MCLab for synthesis of the AxxQ mutant. We thank Rhea Markowitz and Diana G Westbrook for manuscript editing. We are grateful for the help of Mei H Lai at Eli Lilly and Company, and Fermina Mazzella, Jin-Xiong She, Zixuan Wang, Kimberly Smith, and Doris Cawley at Medical College of Georgia. Zheqiong Yang is an exchange trainee from Wuhan University, China.

Author information

Authors and Affiliations

  1. Department of Pathology, Medical College of Georgia, Augusta, GA, USA

    Y Sui, Z Yang, S Xiong, S C Peiper & L Ko

  2. Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA, USA

    Y Sui, Z Yang, S Xiong, S C Peiper, W S Dynan & L Ko

  3. Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA, USA

    L Zhang & D Tuan

  4. Lilly Research Laboratories, Indianapolis, IN, USA

    K L Blanchard

Authors
  1. Y Sui
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Z Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K L Blanchard
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S C Peiper
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. W S Dynan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. D Tuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. L Ko
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L Ko.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sui, Y., Yang, Z., Xiong, S. et al. Gene amplification and associated loss of 5′ regulatory sequences of CoAA in human cancers. Oncogene 26, 822–835 (2007). https://doi.org/10.1038/sj.onc.1209847

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1209847

Keywords

This article is cited by

Search

Advanced search

Quick links