Skip to main content
SpringerLink
Log in

Human CMTM2/CKLFSF2 enhances the ligand-induced transactivation of the androgen receptor

  • Articles/Molecular Biology
  • Published:
Chinese Science Bulletin

Abstract

CKLF (chemokine-like factor)-like MARVEL (MAL and related proteins for vesicle trafficking and membrane link domain) transmembrane domain containing (CMTM) is a novel gene family. One member of this family, CMTM2, also named chemokine-like factor superfamily 2 (CKLFSF2), is expressed highly in the testis and moderately in the prostate, marrow and peripheral blood cells. However, the function of human CMTM2 remains unknown. Here, we found that CMTM2 was upregulated in 5α-dihydrotestosterone (DHT)-treated LNCaP cells. We investigated the relationship between CMTM2 and the androgen receptor. Our results showed that CMTM2 enhanced DHT-mediated androgen receptor (AR) transactivation and the expression of prostate specific antigen (PSA). We also observed that CMTM2 enhanced the AR protein level, which was reversed by silencing endogenous CMTM2 expression, which suggested that CMTM2 might play an important role in maintaining the AR protein level. We also found that CMTM2 suppressed Akt activation. A previous study showed that Akt could phosphorylate AR at Ser210 and Ser790 and lead to AR ubiquitylation and degradation as well as suppression of AR activity. Taken together, suppressing Akt activation and increasing the AR protein level might be one of the mechanisms for the CMTM2-mediated enhancement of AR transactivation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Voegeli T A, Kurtz A, Grimm M O, et al. Anemia under androgen deprivation: influence of flutamide, cyproteroneacetate and orchiectomy on the erythropoietin system. Horm Metab Res, 2005 37, 89–93

    Article  Google Scholar 

  2. Smith H R, Steinberg A D. Autoimmunity-a perspective. Annu Rev Immunol, 1983 1, 175–210

    Article  Google Scholar 

  3. Roy A K, Lavrovsky Y, Song C S, et al. Regulation of androgen action. Vitam Horm, 1999 55, 309–352

    Article  Google Scholar 

  4. Tilley W D, Marcelli M, Wilson J D, et al. Characterization and expression of a cDNA encoding the human androgen receptor. Proc Natl Acad Sci USA, 1989 86, 327–331

    Article  Google Scholar 

  5. Langley E, Zhou Z X, Wilson E M. Evidence for an anti-parallel orientation of the ligand-activated human androgen receptor dimer. J Biol Chem, 1995 270, 29983–29990

    Article  Google Scholar 

  6. Heemers H V, Tindall D J. Androgen receptor (AR) coregulators: a diversity of functions converging on and regulating the AR transcriptional complex. Endocr Rev, 2007 28, 778–808

    Article  Google Scholar 

  7. Lee H J, Chang C. Recent advances in androgen receptor action. Cell Mol Life Sci, 2003 60, 1613–1622

    Article  Google Scholar 

  8. Rachez C, Gamble M, Chang C P, et al. The DRIP complex and SRC-1/p160 coactivators share similar nuclear receptor binding determinants but constitute functionally distinct complexes. Mol Cell Biol, 2000 20, 2718–2726

    Article  Google Scholar 

  9. Yeh S, Chang C. Cloning and characterization of a specific coactivator, ARA70, for the androgen receptor in human prostate cells. Proc Natl Acad Sci USA, 1996 93, 5517-5521

    Article  Google Scholar 

  10. Torchia J, Rose D W, Inostroza J, et al. The transcriptional co-activator p/CIP binds CBP and mediates nuclear-receptor function. Nature, 1997 387, 677–684

    Article  Google Scholar 

  11. Heery D M, Kalkhoven E, Hoare S, et al. A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature, 1997 387, 733–736

    Article  Google Scholar 

  12. Hsu C L, Chen Y L, Yeh S, et al. The use of phage display technique for the isolation of androgen receptor interacting peptides with (F/W)XXL(F/W) and FXXLY new signature motifs. J Biol Chem, 2003 278, 23691–23698

    Article  Google Scholar 

  13. van de Wijngaart, Dennis J, van Royen, et al. Novel FXXFF and FXXMF motifs in androgen receptor cofactors mediate high affinity and specific interactions with the ligand-binding domain. J Biol Chem, 2006 281, 19407–19416

    Article  Google Scholar 

  14. Han W, Ding P, Xu M, et al. Identification of eight genes encoding chemokine-like factor superfamily members 1-8 (CKLFSF1-8) by in silico cloning and experimental validation. Genomics, 2003 81, 609–617

    Article  Google Scholar 

  15. Han W, Lou Y, Tang J, et al. Molecular cloning and characterization of chemokine-like factor 1 (CKLF1), a novel human cytokine with unique structure and potential chemotactic activity. Biochem J, 2001 357, 127–135

    Article  Google Scholar 

  16. Wang Y, Li T, Qiu X, et al. CMTM3 can affect the transcription activity of androgen receptor and inhibit the expression level of PSA in LNCaP cells. Biochem Biophys Res Commun, 2008 371, 54–58

    Article  Google Scholar 

  17. Zhu B, Li T, Zhou Y, et al. CMTM1-v17, a new potential corepressor of androgen receptor (in Chinese). J Pek Univ (Health Sci), 2007 39, 388–393

    Google Scholar 

  18. Shi S, Rui M, Han W, et al. CKLFSF2 is highly expressed in testis and can be secreted into the seminiferous tubules. Int J Biochem Cell Biol, 2005 37, 1633–1640

    Article  Google Scholar 

  19. Liu G, Xin Z C, Chen L, et al. Expression and localization of CKLFSF2 in human spermatogenesis. Asian J Androl, 2007 30, 189–198

    Article  Google Scholar 

  20. Li T, Han W, Yang T, et al. Molecular cloning and identification of mouse Cklfsf2a and Cklfsf2b, two homologues of human CKLFSF2. Int J Biochem Cell Biol, 2006 38, 420–429

    Article  Google Scholar 

  21. Jeong B C, Hong C Y, Chattopadhyay S, et al. Androgen receptor corepressor-19 kDa (ARR19), a leucine-rich protein that represses the transcriptional activity of androgen receptor through recruitment of histone deacetylase. Mol Endocrinol, 2004 18, 13-25

    Article  Google Scholar 

  22. Hosoya T, Monden T, Fukabori Y, et al. A novel splice variant of the nuclear coactivator p120 functions strongly for androgen receptor: characteristic expression in prostate disease. Endocr J, 2008 55, 657–665

    Article  Google Scholar 

  23. Lee C, Sutkowski D M, Sensibar J A, et al. Regulation of proliferation and production of prostate-specific antigen in androgen-sensitive prostatic cancer cells, LNCaP, by dihydrotestosterone. Endocrinology, 1995 136, 796–803

    Article  Google Scholar 

  24. Sica G, Iacopino F, Settesoldi D, et al. Effect of leuprorelin acetate on cell growth and prostate-specific antigen gene expression in human prostatic cancer cells. Eur Urol, 1999 35, 2–8

    Article  Google Scholar 

  25. de Launoit Y, Veilleux R, Dufour M, et al. Characteristics of the Biphasic action of androgens and of the potent antiproliferative effects of the new pure antiestrogen EM-139 on cell cycle kinetic parameters in LNCaP human prostatic cancer cells. Cancer Res, 1991 51, 5165–5170

    Google Scholar 

  26. Shao C, Wang Y, Yue H H, et al. Biphasic effect of androgens on prostate cancer cells and its correlation with androgen receptor coactivator dopa decarboxylase. J Androl, 2007 28, 804–812

    Article  Google Scholar 

  27. Yu F X, Sun H Q, Janmey P A, et al. Identification of a polyphosphoinositide-binding sequence in an actin monomer-binding domain of gelsolin. J Biol Chem, 1992 267, 14616–14621

    Google Scholar 

  28. Janmey P A, Lamb J, Allen P G, et al. Phosphoinositide-binding peptides derived from the sequences of gelsolin and villin. J Biol Chem, 1992 267, 11818–11823

    Google Scholar 

  29. Ching T T, Lin H P, Yang C C, et al. Specific binding of the C-terminal Src homology 2 domain of the p85alpha subunit of phosphoinositide 3-kinase to phosphatidylinositol 3,4,5-trisphosphate. Localization and engineering of the phosphoinositide-binding motif. J Biol Chem, 2001 276, 43932–43938

    Google Scholar 

  30. Stambolic V, Suzuki A, de la Pompa J L, et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell, 1998 95, 29–39

    Article  Google Scholar 

  31. Maehama T, Dixon J E. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem, 1998 273, 13375–13378

    Article  Google Scholar 

  32. McConnachie G, Pass I, Walker S M, et al. Interfacial kinetic analysis of the tumour suppressor phosphatase, PTEN: evidence for activation by anionic phospholipids. Biochem J, 2003 371, 947–955

    Article  Google Scholar 

  33. Campbell R B, Liu F, Ross A H. Allosteric activation of PTEN phosphatase by phosphatidylinositol 4,5-bisphosphate. J Biol Chem, 2003 278, 33617–33620

    Article  Google Scholar 

  34. Lin H K, Yeh S, Kang H Y, et al. Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Proc Natl Acad Sci USA, 2001 98, 7200–7205

    Article  Google Scholar 

  35. Lin H K, Wang L, Hu Y C, et al. Phosphorylation-dependent ubiquitylation and degradation of androgen receptor by Akt require Mdm2 E3 ligase. EMBO J, 2002 21, 4037–4048

    Article  Google Scholar 

  36. Hu Y C, Yeh S, Yeh S D, et al. Functional domain and motif analyses of androgen receptor coregulator ARA70 and its differential expression in prostate cancer. J Biol Chem, 2004 279, 33438–33446

    Article  Google Scholar 

  37. Mohler J L, Chen Y, Hamil K, et al. Androgen and glucocorticoid receptors in the stroma and epithelium of prostatic hyperplasia and carcinoma. Clin Cancer Res, 1996 2, 889–895

    Google Scholar 

  38. Yeh S, Miyamoto H, Nishimura K, et al. Retinoblastoma, a tumor suppressor, is a coactivator for the androgen receptor in human prostate cancer DU145 cells. Biochem Biophys Res Commun, 1998 248, 361–367

    Article  Google Scholar 

  39. Yeh S, Hu Y C, Rahman M, et al. Increase of androgen-induced cell death and androgen receptor transactivation by BRCA1 in prostate cancer cells. Proc Natl Acad Sci USA, 2000 97, 11256–11261

    Article  Google Scholar 

  40. Shin S, Verma I M. BRCA2 cooperates with histone acetyltransferases in androgen receptor-mediated transcription. Proc Natl Acad Sci USA, 2003 100, 7201–7206

    Article  Google Scholar 

  41. Wang X, Deng H, Basu I, et al. Induction of androgen receptor-dependent apoptosis in prostate cancer cells by the retinoblastoma protein. Cancer Res, 2004 64, 1377–1385

    Article  Google Scholar 

  42. Lin J, Adam R M, Santiestevan E, et al. The phosphatidylinositol 3’-kinase pathway is a dominant growth factor-activated cell survival pathway in LNCaP human prostate carcinoma cells. Cancer Res, 1999 59, 2891–2897

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Urology, First Hospital of Peking University, Beijing, 100034, China

    DaZhen Liu & YingLu Guo

  2. Department of Medical Immunology, School of Basic Medical Science, Peking University Health Science Center, Beijing, 100083, China

    CaiHua Yin, LinJie Tian, Dan Li, DaLong Ma & Ying Wang

  3. Center for Human Disease Genomics, Peking University, Beijing, 100083, China

    YingMei Zhang, Ting Li, DaLong Ma & Ying Wang

  4. Department of Urology, General Hospital of Tianjin Medical University, Tianjin, 300052, China

    DaZhen Liu

Authors
  1. DaZhen Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. CaiHua Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. YingMei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. LinJie Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ting Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. DaLong Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. YingLu Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ying Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ying Wang.

Additional information

Supported by National High Technology Research and Development Program of China (Grant Nos. 2006AA02A305 and 2002BA711A01) and National Natural Science Foundation of China (Grant Nos. 30271203 and 30671907)

About this article

Cite this article

Liu, D., Yin, C., Zhang, Y. et al. Human CMTM2/CKLFSF2 enhances the ligand-induced transactivation of the androgen receptor. Chin. Sci. Bull. 54, 1050–1057 (2009). https://doi.org/10.1007/s11434-009-0092-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11434-009-0092-8

Keywords

Search

Navigation