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:

Zipper-interacting protein kinase is involved in regulation of ubiquitination of the androgen receptor, thereby contributing to dynamic transcription complex assembly

Oncogene volume 32, pages 4981–4988 (2013)Cite this article

Subjects

Abstract

We have recently identified apoptosis-antagonizing transcription factor (AATF), tumor-susceptibility gene 101 (TSG101) and zipper-interacting protein kinase (ZIPK) as novel coactivators of the androgen receptor (AR). The mechanisms of coactivation remained obscure, however. Here we investigated the interplay and interdependence between these coactivators and the AR using the endogenous prostate specific antigen (PSA) gene as model for AR-target genes. Chromatin immunoprecipitation in combination with siRNA-mediated knockdown revealed that recruitment of AATF and ZIPK to the PSA enhancer was dependent on AR, whereas recruitment of TSG101 was dependent on AATF. Association of AR and its coactivators with the PSA enhancer or promoter occurred in cycles. Dissociation of AR-transcription complexes was due to degradation because inhibition of the proteasome system by MG132 caused accumulation of AR at enhancer/promoter elements. Moreover, inhibition of degradation strongly reduced transcription, indicating that continued and efficient transcription is based on initiation, degradation and reinitiation cycles. Interestingly, knockdown of ZIPK by siRNA had a similar effect as MG132, leading to reduced transcription but enhanced accumulation of AR at androgen-response elements. In addition, knockdown of ZIPK, as well as overexpression of a dominant-negative ZIPK mutant, diminished polyubiquitination of AR. Furthermore, ZIPK cooperated with the E3 ligase Mdm2 in AR-dependent transactivation, assembled into a single complex on chromatin and phosphorylated Mdm2 in vitro. These results suggest that ZIPK has a crucial role in regulation of ubiquitination and degradation of the AR, and hence promoter clearance and efficient transcription.

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

Similar content being viewed by others

References

  1. Heemers HV, Tindall DJ . Androgen receptor (AR) coregulators: a diversity of functions converging on and regulating the AR transcriptional complex. Endocr Rev 2007; 28: 778–808.

    Article  CAS  Google Scholar 

  2. Faus H, Haendler B . Post-translational modifications of steroid receptors. Biomed Pharmacother 2006; 60: 520–528.

    Article  CAS  Google Scholar 

  3. Gioeli D, Paschal BM . Post-translational modification of the androgen receptor. Mol Cell Endocrinol 2012; 352: 70–78.

    Article  CAS  Google Scholar 

  4. Hinojos CA, Sharp ZD, Mancini MA . Molecular dynamics and nuclear receptor function. Trends Endocrinol Metab 2005; 16: 12–18.

    Article  CAS  Google Scholar 

  5. Johnsen SA, Kangaspeska S, Reidt G, Gannon F . Interfering with the dynamics of estrogen receptor-regulated transcription. Ernst Schering Found Symp Proc 2006; 1: 1–12.

    Google Scholar 

  6. Shang Y, Hu X, DiRenzo J, Lazar MA, Brown M . Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription. Cell 2000; 103: 843–852.

    Article  CAS  Google Scholar 

  7. Reid G, Hubner MR, Métivier R, Brand H, Denger S, Manu D et al. Cyclic, proteasome-mediated turnover of unliganded and liganded ERalpha on responsive promoters is an integral feature of estrogen signaling. Mol Cell 2003; 11: 695–707.

    Article  CAS  Google Scholar 

  8. Métivier R, Penot G, Hubner MR, Reid G, Brand H, Kos M et al. Estrogen receptor-alpha directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter. Cell 2003; 115: 751–763.

    Article  Google Scholar 

  9. Wang Q, Carroll JS, Brown M . Spatial and temporal recruitment of androgen receptor and its coactivators involves chromosomal looping and polymerase tracking. Mol Cell 2005; 19: 631–642.

    Article  CAS  PubMed Central  Google Scholar 

  10. Kang Z, Pirskanen A, Janne OA, Palvimo JJ . Involvement of proteasome in the dynamic assembly of the androgen receptor transcription complex. J Biol Chem 2002; 277: 48366–48371.

    Article  CAS  Google Scholar 

  11. Kang Z, Janne OA, Palvimo JJ . Coregulator recruitment and histone modifications in transcriptional regulation by the androgen receptor. Mol Endocrinol 2004; 18: 2633–2648.

    Article  CAS  PubMed Central  Google Scholar 

  12. Welsbie DS, Xu J, Chen Y, Borsu L, Scher HI, Rosen N et al. Histone deacetylases are required for androgen receptor function in hormone-sensitive and castrate-resistant prostate cancer. Cancer Res 2009; 69: 958–966.

    Article  CAS  PubMed Central  Google Scholar 

  13. Keppler BR, Archer TK, Kinyamu HK . Emerging roles of the 26S proteasome in nuclear hormone receptor-regulated transcription. Biochim Biophys Acta 2011; 1809: 109–118.

    Article  CAS  Google Scholar 

  14. Gaughan L, Logan IR, Neal DE, Robson CN . Regulation of androgen receptor and histone deacetylase 1 by Mdm2-mediated ubiquitylation. Nucleic Acids Res 2005; 33: 13–26.

    Article  CAS  PubMed Central  Google Scholar 

  15. Xu K, Shimelis H, Linn DE, Jiang R, Yang X, Sun F et al. Regulation of androgen receptor transcriptional activity and specificity by RNF6-induced ubiquitination. Cancer Cell 2009; 15: 270–282.

    Article  CAS  PubMed Central  Google Scholar 

  16. Leister P, Burgdorf S, Scheidtmann KH . Apoptosis antagonizing transcription factor AATF is a novel co-activator of nuclear hormone receptors. Signal Transduction 2003; 3: 17–25.

    Article  CAS  Google Scholar 

  17. Burgdorf S, Leister P, Scheidtmann KH . TSG101 interacts with apoptosis-antagonizing transcription factor and enhances androgen receptor-mediated transcription by promoting its monoubiquitination. J Biol Chem 2004; 279: 17524–17534.

    Article  CAS  PubMed Central  Google Scholar 

  18. Leister P, Felten A, Chasan AI, Scheidtmann KH . ZIP kinase plays a crucial role in androgen receptor-mediated transcription. Oncogene 2008; 27: 3292–3300.

    Article  CAS  Google Scholar 

  19. Page G, Lodige I, Kogel D, Scheidtmann KH . AATF, a novel transcription factor that interacts with Dlk/ZIP kinase and interferes with apoptosis. FEBS Lett 1999b; 462: 187–191.

    Article  CAS  PubMed Central  Google Scholar 

  20. Passananti C, Floridi A, Fanciulli M . Che-1/AATF, a multivalent adaptor connecting transcriptional regulation, checkpoint control, and apoptosis. Biochem Cell Biol 2007; 85: 477–483.

    Article  CAS  Google Scholar 

  21. Bruno T, De Angelis R, De Nicola F, Barbato C, Di Padova M, Corbi N et al. Che-1 affects cell growth by interfering with the recruitment of HDAC1 by Rb. Cancer Cell 2002; 2: 387–399.

    Article  CAS  PubMed Central  Google Scholar 

  22. Di Padova M, Bruno T, De Nicola F, Iezzi S, D'Angelo C, Gallo R et al. Che-1 arrests human colon carcinoma cell proliferation by displacing HDAC1 from the p21WAF1/CIP1 promoter. J Biol Chem 2003; 278: 36496–36504.

    Article  CAS  PubMed Central  Google Scholar 

  23. Scheidtmann KH . Dlk/ZIP kinase, a novel Ser/Thr-specific protein kinase with multiple functions. Signal Transduction 2007; 7: 248–259.

    Article  CAS  Google Scholar 

  24. Brognard J, Zhang YW, Puto LA, Hunter T . Cancer-associated loss-of-function mutations implicate DAPK3 as a tumor-suppressing kinase. Cancer Res 2011; 71: 3152–3161.

    Article  CAS  PubMed Central  Google Scholar 

  25. Bi J, Lau SH, Hu L, Rao HL, Liu HB, Zhan WH et al. Downregulation of ZIP kinase is associated with tumor invasion, metastasis and poor prognosis in gastric cancer. Int J Cancer 2009; 124: 1587–1593.

    Article  CAS  Google Scholar 

  26. Natrajan R, Mackay A, Lambros MB, Weigelt B, Wilkerson PM, Manie E et al. A whole-genome massively parallel sequencing analysis of BRCA1 mutant oestrogen receptor-negative and -positive breast cancers. J Pathol 2012; 227: 29–41.

    Article  CAS  PubMed Central  Google Scholar 

  27. Kawai T, Matsumoto M, Takeda K, Sanjo H, Akira S . ZIP kinase, a novel serine/threonine kinase which mediates apoptosis. Mol Cell Biol 1998; 18: 1642–1651.

    Article  CAS  PubMed Central  Google Scholar 

  28. Sato N, Kawai T, Sugiyama K, Muromoto R, Imoto S, Sekine Y et al. Physical and functional interactions between STAT3 and ZIP kinase. Int Immunol 2005; 17: 1543–1552.

    Article  CAS  PubMed Central  Google Scholar 

  29. Engemann H, Heinzel V, Page G, Preuss U, Scheidtmann KH . DAP-like kinase interacts with the rat homolog of Schizosaccharomyces pombe CDC5 protein, a factor involved in pre-mRNA splicing and required for G2/M phase transition. Nucleic Acids Res 2002; 30: 1408–1417.

    Article  CAS  PubMed Central  Google Scholar 

  30. De Nicola F, Bruno T, Iezzi S, Di Padova M, Floridi A, Passananti C et al. The prolyl isomerase Pin1 affects Che-1 stability in response to apoptotic DNA damage. J Biol Chem 2007; 282: 19685–19691.

    Article  CAS  Google Scholar 

  31. Li L, Liao J, Ruland J, Mak TW, Cohen SNA . TSG101/MDM2 regulatory loop modulates MDM2 degradation and MDM2/p53 feedback control. Proc Natl Acad Sci USA 2001; 98: 1619–1624.

    Article  CAS  Google Scholar 

  32. Lin HK, Wang L, Hu YC, Altuwaijri S, Chang C . Phosphorylation-dependent ubiquitylation and degradation of androgen receptor by Akt require Mdm2 E3 ligase. EMBO J 2002b; 21: 4037–4048.

    Article  CAS  PubMed Central  Google Scholar 

  33. Burch LR, Scott M, Pohler E, Meek D, Hupp T . Phage-peptide display identifies the interferon-responsive, death-activated protein kinase family as a novel modifier of MDM2 and p21WAF1. J Mol Biol 2004; 337: 115–128.

    Article  CAS  Google Scholar 

  34. Saji S, Okumura N, Eguchi H, Nakashima S, Suzuki A, Toi M et al. MDM2 enhances the function of estrogen receptor alpha in human breast cancer cells. Biochem Biophys Res Commun 2001; 281: 259–265.

    Article  CAS  Google Scholar 

  35. Sharma D, Fondell JD . Ordered recruitment of histone acetyltransferases and the TRAP/Mediator complex to thyroid hormone-responsive promoters in vivo. Proc Natl Acad Sci USA 2002; 99: 7934–7939.

    Article  CAS  Google Scholar 

  36. Vaisanen S, Dunlop TW, Sinkkonen L, Frank C, Carlberg C . Spatio-temporal activation of chromatin on the human CYP24 gene promoter in the presence of 1alpha,25-dihydroxyvitamin D3. J Mol Biol 2005; 350: 65–77.

    Article  CAS  Google Scholar 

  37. Lin HK, Altuwaijri S, Lin WJ, Kan PY, Collins LL, Chang C . Proteasome activity is required for androgen receptor transcriptional activity via regulation of androgen receptor nuclear translocation and interaction with coregulators in prostate cancer cells. J Biol Chem 2002a; 277: 36570–36576.

    Article  CAS  Google Scholar 

  38. Chymkowitch P, Le May N, Charneau P, Compe E, Egly JM . The phosphorylation of the androgen receptor by TFIIH directs the ubiquitin/proteasome process. EMBO J 2011; 30: 468–479.

    Article  CAS  Google Scholar 

  39. Graves PR, Winkfield KM, Haystead TA . Regulation of zipper-interacting protein kinase activity in vitro and in vivo by multisite phosphorylation. J Biol Chem 2005; 280: 9363–9374.

    Article  CAS  Google Scholar 

  40. Felten A, Leister P, Burgdorf S, Uhlmann L, Scheidtmann KH . Characterization of rat BLOS2/Ceap, a putative yeast She3 homolog, as interaction partner of apoptosis antagonizing transcription factor/Che-1. Biol Chem 2007; 388: 569–582.

    Article  CAS  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Dr Klemens Rottner and Dr Walter Witke from the Institute of Genetics (Bonn, Germany) for their hospitality during revision and Dr Maurizio Fanciulli (Regina Elena Cancer Institute, Rome, Italy) for antibodies against AATF/Che-1. This work was supported by the German Research Association to KHS (Sche246/20–1).

Author information

Author notes

  1. A Felten

    Present address: 2Current address: Center for Economics and Neuroscience, University of Bonn, Bonn, Germany.,

  2. D Brinckmann

    Present address: 3Current address: soITbe IT-Solutions, Rhenusallee 25, Bonn, Germany.,

Authors and Affiliations

  1. Institute of Genetics, University of Bonn, Bonn, Germany

    A Felten, D Brinckmann, G Landsberg & K H Scheidtmann

Authors
  1. A Felten
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D Brinckmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G Landsberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K H Scheidtmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A Felten.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Felten, A., Brinckmann, D., Landsberg, G. et al. Zipper-interacting protein kinase is involved in regulation of ubiquitination of the androgen receptor, thereby contributing to dynamic transcription complex assembly. Oncogene 32, 4981–4988 (2013). https://doi.org/10.1038/onc.2012.503

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2012.503

Keywords

Search

Advanced search

Quick links