Specific Properties of a C-terminal Truncated Androgen Receptor Detected in Hormone Refractory Prostate Cancer

  • Gaëlle Lapouge
  • Gemma Marcias
  • Eva Erdmann
  • Pascal Kessler
  • Marion Cruchant
  • Sebastian Serra
  • Jean-Pierre Bergerat
  • Jocelyn Céraline
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 617)


Mutations in the human androgen receptor (AR) gene that lead to C-terminus truncated AR variants are frequently detected in prostate cancer (PC). These AR variants lack both the ligand-binding domain (LBD) and the AF-2 region. The aim of this study was to delineate the alternative mechanisms that lead to the activation of such AR variants as they are unresponsive to hormone stimulation, and to outline consequences of the loss of the LBD/AF-2 region on their functional properties. By using an MMTV-luciferase reporter construct and LY294002, UO126, or ZD1839, inhibitor of PI3K, MEK1/2, and EGFR signaling pathway respectively, we demonstrated that phosphorylation was required for full transcriptional activities of one these AR variants, the Q640X mutant AR. Western-blot analyses confirmed that these inhibitors affect the phosphorylation status of this AR variant. Furthermore, studies of the intranuclear colocalization of the Q640X AR with cofactors, such as CBP, GRIP-1, and c-Jun, reveal that the transcriptional complex that forms around the mutant AR is different to that formed around the wild type AR. We demonstrated that CBP and c-Jun are highly recruited by the mutant AR, and this leads to an unexpected activation of AP-1, NFAT, and NFκB transcriptional activities. Similar enhanced activities of these transcription factors were not observed with the wild type AR. The importance of the LBD/AF-2 for the regulation of AR transcriptional activities, the impact of the presence of such AR variants on PC cells proliferation and survival, and on progression to androgen independence are discussed.


Epidermal Growth Factor Receptor Androgen Receptor Epidermal Growth Factor Receptor Signaling Pathway Human Androgen Receptor Mutant Androgen Receptor 
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  1. 1.
    Gioeli D, Ficarro SB, Kwiek JJ, et al. (2002) Androgen receptor phosphorylation. Regulation and identification of the phosphorylation sites. J Biol Chem. 277, 29304–29314.PubMedCrossRefGoogle Scholar
  2. 2.
    Culig Z, Steiner H, Bartsch G, et al. (2005) Mechanisms of endocrine therapy-responsive and -unresponsive prostate tumours. Endocr Relat Cancer. 12, 229–244.PubMedCrossRefGoogle Scholar
  3. 3.
    Heinlein CA, Chang C (2002) Androgen receptor (AR) coregulators: an overview. Endocr Rev. 23, 175–200.PubMedCrossRefGoogle Scholar
  4. 4.
    Bubulya A, Chen SY, Fisher CJ, et al. (2001) c-Jun potentiates the functional interaction between the amino and carboxyl termini of the androgen receptor. J Biol Chem. 276, 44704–44711.PubMedCrossRefGoogle Scholar
  5. 5.
    Ceraline J, Cruchant MD, Erdmann E, et al. (2004) Constitutive activation of the androgen receptor by a point mutation in the hinge region: a new mechanism for androgen-independent growth in prostate cancer. Int J Cancer. 108, 152–157.PubMedCrossRefGoogle Scholar
  6. 6.
    Taneja SS, Ha S, Swenson NK, et al. (2005) Cell-specific regulation of androgen receptor phosphorylation in vivo. J Biol Chem. 280, 40916–40924.PubMedCrossRefGoogle Scholar
  7. 7.
    Wen Y, Hu MC, Makino K, et al. (2000) HER-2/neu promotes androgen-independent survival and growth of prostate cancer cells through the Akt pathway. Cancer Res. 60(24), 6841–6845.PubMedGoogle Scholar
  8. 8.
    Lin HK, Yeh S, Kang HY, et al. (2001) Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Proc Natl Acad Sci USA. 98(13), 7200–7205.PubMedCrossRefGoogle Scholar
  9. 9.
    LaFevre-Bernt MA, Ellerby LM (2003) Kennedy’s disease. Phosphorylation of the polyglutamine-expanded form of androgen receptor regulates its cleavage by caspase-3 and enhances cell death. J Biol Chem. 278(37), 34918–34924.PubMedCrossRefGoogle Scholar
  10. 10.
    He B, Kemppainen JA, Voegel JJ, et al. (1999) Activation function 2 in the human androgen receptor ligand binding domain mediates interdomain communication with the NH(2)-terminal domain. J Biol Chem. 274, 37219–37225.PubMedCrossRefGoogle Scholar
  11. 11.
    Ikonen T, Palvimo JJ, Janne OA (1997) Interaction between the amino- and carboxyl-terminal regions of the rat androgen receptor modulates transcriptional activity and is influenced by nuclear receptor coactivators. J Biol Chem. 272, 29821–29828.PubMedCrossRefGoogle Scholar
  12. 12.
    Berrevoets CA, Doesburg P, Steketee K, et al. (1998) Functional interactions of the AF-2 activation domain core region of the human androgen receptor with the amino-terminal domain and with the transcriptional coactivator TIF2 (transcriptional intermediary factor2). Mol Endocrinol. 12, 1172–1183.PubMedCrossRefGoogle Scholar
  13. 13.
    Eferl R, Wagner EF (2003) AP-1: a double-edged sword in tumorigenesis Nat Rev Cancer. 3(11), 859–868.PubMedCrossRefGoogle Scholar
  14. 14.
    Ghosh S, Karin M (2002) Missing Pieces in the NF-κB Puzzle. Cell. 109 (Suppl): S81–S96.PubMedCrossRefGoogle Scholar
  15. 15.
    Rao A, Luo C, Hogan PG (1997) Transcription factors of the NFAT family: regulation and function. Annu Rev Immunol. 15, 707–747.PubMedCrossRefGoogle Scholar
  16. 16.
    Hogan PG, Chen L, Nardone J, et al. (2003) Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev. 17(18), 2205–2232.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  • Gaëlle Lapouge
    • 1
  • Gemma Marcias
  • Eva Erdmann
  • Pascal Kessler
  • Marion Cruchant
  • Sebastian Serra
  • Jean-Pierre Bergerat
  • Jocelyn Céraline
  1. 1.Laboratoire de Cancerologie Experimentale et de RadiobiologieStrasbourgFrance

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