Identification of RBCK1 as a novel regulator of FKBPL: Implications for tumor growth and response to tamoxifen

C. Donley, K. McClelland, H. D. McKeen, L. Nelson, A. Yakkundi, P. V. Jithesh, J. Burrows, L. McClements, A. Valentine, K. M. Prise, H. O. McCarthy, T. Robson

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

FKBPL has been implicated in processes associated with cancer, including regulation of tumor growth and angiogenesis with high levels of FKBPL prognosticating for improved patient survival. Understanding how FKBPL levels are controlled within the cell is therefore critical. We have identified a novel role for RBCK1 as an FKBPL-interacting protein, which regulates FKBPL stability at the post-translational level via ubiquitination. Both RBCK1 and FKBPL are upregulated by 17-b-estradiol and interact within heat shock protein 90 chaperone complexes, together with estrogen receptor-α (ERα). Furthermore, FKBPL and RBCK1 associate with ERα at the promoter of the estrogen responsive gene, pS2, and regulate pS2 levels. MCF-7 clones stably overexpressing RBCK1 were shown to have reduced proliferation and increased levels of FKBPL and p21. Furthermore, these clones were resistant to tamoxifen therapy, suggesting that RBCK1 could be a predictive marker of response to endocrine therapy. RBCK1 knockdown using targeted small interfering RNA resulted in increased proliferation and increased sensitivity to tamoxifen treatment. Moreover, in support of our in vitro data, analysis of mRNA microarray data sets demonstrated that high levels of FKBPL and RBCK1 correlated with increased patient survival, whereas high RBCK1 predicted for a poor response to tamoxifen. Our findings support a role for RBCK1 in the regulation of FKBPL with important implications for estrogen receptor signaling, cell proliferation and response to endocrine therapy.

Original languageEnglish
Pages (from-to)3441-3450
Number of pages10
JournalBritish Dental Journal
Volume217
Issue number1
DOIs
Publication statusPublished - 11 Jul 2014
Externally publishedYes

Fingerprint

Tamoxifen
Estrogen Receptors
Growth
Neoplasms
Clone Cells
HSP90 Heat-Shock Proteins
Survival
Ubiquitination
Therapeutics
Small Interfering RNA
Estradiol
Estrogens
Cell Proliferation
Messenger RNA
Genes
Proteins

Keywords

  • estrogen receptor
  • FKBPL
  • p21
  • RBCK1
  • tamoxifen

ASJC Scopus subject areas

  • Dentistry(all)

Cite this

Identification of RBCK1 as a novel regulator of FKBPL : Implications for tumor growth and response to tamoxifen. / Donley, C.; McClelland, K.; McKeen, H. D.; Nelson, L.; Yakkundi, A.; Jithesh, P. V.; Burrows, J.; McClements, L.; Valentine, A.; Prise, K. M.; McCarthy, H. O.; Robson, T.

In: British Dental Journal, Vol. 217, No. 1, 11.07.2014, p. 3441-3450.

Research output: Contribution to journalArticle

Donley, C, McClelland, K, McKeen, HD, Nelson, L, Yakkundi, A, Jithesh, PV, Burrows, J, McClements, L, Valentine, A, Prise, KM, McCarthy, HO & Robson, T 2014, 'Identification of RBCK1 as a novel regulator of FKBPL: Implications for tumor growth and response to tamoxifen', British Dental Journal, vol. 217, no. 1, pp. 3441-3450. https://doi.org/10.1038/onc.2013.306
Donley, C. ; McClelland, K. ; McKeen, H. D. ; Nelson, L. ; Yakkundi, A. ; Jithesh, P. V. ; Burrows, J. ; McClements, L. ; Valentine, A. ; Prise, K. M. ; McCarthy, H. O. ; Robson, T. / Identification of RBCK1 as a novel regulator of FKBPL : Implications for tumor growth and response to tamoxifen. In: British Dental Journal. 2014 ; Vol. 217, No. 1. pp. 3441-3450.
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