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Y-box binding protein-1 serine 102 is a downstream target of p90 ribosomal S6 kinase in basal-like breast cancer cells.
Breast Cancer Res. 2008; 10(6):R99.BC

Abstract

INTRODUCTION

Basal-like breast cancers (BLBC) frequently overexpress the epidermal growth factor receptor (EGFR) and subsequently have high levels of signaling through the MAP kinase pathway, which is thought to contribute to their aggressive behavior. While we have previously reported the expression of Y-box binding protein-1 (YB-1) in 73% of BLBC, it is unclear whether it can be regulated by a component of the MAP kinase signaling pathway. Phosphorylation of YB-1 at the serine 102 residue is required for transcriptional activation of growth-enhancing genes, such as EGFR. Using Motifscan we identified p90 ribosomal S6 kinase (RSK) as a potential candidate for activating YB-1.

METHODS

Inhibition of RSK1 and RSK2 was achieved using siRNA and the small molecule SL0101. RSK1, RSK2, activated RSK and kinase-dead RSK were expressed in HCC1937 cells. Kinase assays were performed to illustrate direct phosphorylation of YB-1 by RSK. The impact of inhibiting RSK on YB-1 function was measured by luciferase assays and chromatin immunoprecipitation.

RESULTS

Using an in vitro kinase assay, RSK1 and RSK2 were shown to directly phosphorylate YB-1. Interestingly, they were more effective activators of YB-1 than AKT or another novel YB-1 kinase, PKC alpha. Phosphorylation of YB-1 (serine 102 residue) is blocked by inhibition of the MAP kinase pathway or by perturbing RSK1/RSK2 with siRNA or SL0101. In immortalized breast epithelial cells where RSK is active yet AKT is not, YB-1 is phosphorylated. Supporting this observation, RSK2-/- mouse embryo fibroblasts lose the ability to phosphorylate YB-1 in response to epidermal growth factor. This subsequently interfered with the ability of YB-1 to regulate the expression of EGFR. The RSK inhibitor SL0101 decreased the ability of YB-1 to bind the promoter, transactivate and ultimately reduce EGFR expression. In concordance with these results the expression of constitutively active RSK1 increased YB-1 phosphorylation, yet the kinase-dead RSK did not.

CONCLUSIONS

We therefore conclude that RSK1/RSK2 are novel activators of YB-1, able to phosphorylate the serine 102 residue. This provides a newly described mechanism whereby YB-1 is activated in breast cancer. This implicates the EGFR/RSK/YB-1 pathway as an important component of BLBC, providing an important opportunity for therapeutic intervention.

Authors+Show Affiliations

Laboratory for Oncogenomic Research, Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19036157

Citation

Stratford, Anna L., et al. "Y-box Binding Protein-1 Serine 102 Is a Downstream Target of P90 Ribosomal S6 Kinase in Basal-like Breast Cancer Cells." Breast Cancer Research : BCR, vol. 10, no. 6, 2008, pp. R99.
Stratford AL, Fry CJ, Desilets C, et al. Y-box binding protein-1 serine 102 is a downstream target of p90 ribosomal S6 kinase in basal-like breast cancer cells. Breast Cancer Res. 2008;10(6):R99.
Stratford, A. L., Fry, C. J., Desilets, C., Davies, A. H., Cho, Y. Y., Li, Y., Dong, Z., Berquin, I. M., Roux, P. P., & Dunn, S. E. (2008). Y-box binding protein-1 serine 102 is a downstream target of p90 ribosomal S6 kinase in basal-like breast cancer cells. Breast Cancer Research : BCR, 10(6), R99. https://doi.org/10.1186/bcr2202
Stratford AL, et al. Y-box Binding Protein-1 Serine 102 Is a Downstream Target of P90 Ribosomal S6 Kinase in Basal-like Breast Cancer Cells. Breast Cancer Res. 2008;10(6):R99. PubMed PMID: 19036157.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Y-box binding protein-1 serine 102 is a downstream target of p90 ribosomal S6 kinase in basal-like breast cancer cells. AU - Stratford,Anna L, AU - Fry,Christopher J, AU - Desilets,Curtis, AU - Davies,Alastair H, AU - Cho,Yong Y, AU - Li,Yvonne, AU - Dong,Zigang, AU - Berquin,Isabelle M, AU - Roux,Philippe P, AU - Dunn,Sandra E, Y1 - 2008/11/27/ PY - 2008/05/26/received PY - 2008/11/25/revised PY - 2008/11/27/accepted PY - 2008/11/28/entrez PY - 2008/11/28/pubmed PY - 2009/4/8/medline SP - R99 EP - R99 JF - Breast cancer research : BCR JO - Breast Cancer Res. VL - 10 IS - 6 N2 - INTRODUCTION: Basal-like breast cancers (BLBC) frequently overexpress the epidermal growth factor receptor (EGFR) and subsequently have high levels of signaling through the MAP kinase pathway, which is thought to contribute to their aggressive behavior. While we have previously reported the expression of Y-box binding protein-1 (YB-1) in 73% of BLBC, it is unclear whether it can be regulated by a component of the MAP kinase signaling pathway. Phosphorylation of YB-1 at the serine 102 residue is required for transcriptional activation of growth-enhancing genes, such as EGFR. Using Motifscan we identified p90 ribosomal S6 kinase (RSK) as a potential candidate for activating YB-1. METHODS: Inhibition of RSK1 and RSK2 was achieved using siRNA and the small molecule SL0101. RSK1, RSK2, activated RSK and kinase-dead RSK were expressed in HCC1937 cells. Kinase assays were performed to illustrate direct phosphorylation of YB-1 by RSK. The impact of inhibiting RSK on YB-1 function was measured by luciferase assays and chromatin immunoprecipitation. RESULTS: Using an in vitro kinase assay, RSK1 and RSK2 were shown to directly phosphorylate YB-1. Interestingly, they were more effective activators of YB-1 than AKT or another novel YB-1 kinase, PKC alpha. Phosphorylation of YB-1 (serine 102 residue) is blocked by inhibition of the MAP kinase pathway or by perturbing RSK1/RSK2 with siRNA or SL0101. In immortalized breast epithelial cells where RSK is active yet AKT is not, YB-1 is phosphorylated. Supporting this observation, RSK2-/- mouse embryo fibroblasts lose the ability to phosphorylate YB-1 in response to epidermal growth factor. This subsequently interfered with the ability of YB-1 to regulate the expression of EGFR. The RSK inhibitor SL0101 decreased the ability of YB-1 to bind the promoter, transactivate and ultimately reduce EGFR expression. In concordance with these results the expression of constitutively active RSK1 increased YB-1 phosphorylation, yet the kinase-dead RSK did not. CONCLUSIONS: We therefore conclude that RSK1/RSK2 are novel activators of YB-1, able to phosphorylate the serine 102 residue. This provides a newly described mechanism whereby YB-1 is activated in breast cancer. This implicates the EGFR/RSK/YB-1 pathway as an important component of BLBC, providing an important opportunity for therapeutic intervention. SN - 1465-542X UR - https://www.unboundmedicine.com/medline/citation/19036157/Y_box_binding_protein_1_serine_102_is_a_downstream_target_of_p90_ribosomal_S6_kinase_in_basal_like_breast_cancer_cells_ L2 - https://breast-cancer-research.biomedcentral.com/articles/10.1186/bcr2202 DB - PRIME DP - Unbound Medicine ER -