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-β-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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antineoplastic Agents, Hormonal / pharmacology
-
Antineoplastic Agents, Hormonal / therapeutic use*
-
Biomarkers, Tumor / genetics
-
Breast Neoplasms / drug therapy*
-
Breast Neoplasms / genetics
-
Breast Neoplasms / mortality
-
COS Cells
-
Cell Line, Tumor
-
Cell Proliferation
-
Chlorocebus aethiops
-
Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis*
-
Drug Resistance, Neoplasm / genetics*
-
Estradiol / metabolism
-
Female
-
Gene Expression Regulation, Neoplastic
-
HSP90 Heat-Shock Proteins / genetics
-
HSP90 Heat-Shock Proteins / metabolism
-
Humans
-
Immunophilins / biosynthesis
-
Immunophilins / genetics*
-
Neovascularization, Pathologic / genetics
-
Promoter Regions, Genetic / genetics
-
RNA Interference
-
RNA, Small Interfering
-
Receptors, Estrogen / genetics
-
Signal Transduction / genetics
-
Tacrolimus Binding Proteins
-
Tamoxifen / pharmacology
-
Tamoxifen / therapeutic use*
-
Transcription Factors / biosynthesis
-
Transcription Factors / genetics*
-
Transcriptional Activation
-
Treatment Outcome
-
Trefoil Factor-1
-
Tumor Suppressor Proteins / biosynthesis
-
Tumor Suppressor Proteins / genetics
-
Ubiquitin-Protein Ligases
-
Ubiquitination
Substances
-
Antineoplastic Agents, Hormonal
-
Biomarkers, Tumor
-
Cyclin-Dependent Kinase Inhibitor p21
-
FKBPL protein, human
-
HSP90 Heat-Shock Proteins
-
RNA, Small Interfering
-
Receptors, Estrogen
-
TFF1 protein, human
-
Transcription Factors
-
Trefoil Factor-1
-
Tumor Suppressor Proteins
-
Tamoxifen
-
Estradiol
-
RBCK1 protein, human
-
Ubiquitin-Protein Ligases
-
Tacrolimus Binding Proteins
-
Immunophilins