Protein kinase C α regulates nuclear pri-microRNA 15a release as part of endothelin signaling

Melanie Von Brandenstein; Reinhard Depping; Ekaterine Schäfer; Hans Peter Dienes; Jochen W.U. Fries

doi:10.1016/j.bbamcr.2011.06.006

Protein kinase C α regulates nuclear pri-microRNA 15a release as part of endothelin signaling

Melanie Von Brandenstein^*, Reinhard Depping, Ekaterine Schäfer, Hans Peter Dienes, Jochen W.U. Fries

^*Corresponding author for this work

Institute of Physiology

University of Cologne

23 Citations (Scopus)

Abstract

Endothelin-1 induced signaling is characterized by an early induction of a nuclear factor-kappa B p65/mitogen-activated phosphokinase p38 transcription complex via its A-receptor versus a late induction via diacylglycerol, and protein kinase C. A possible interaction between these two pathways and a potential function for protein kinase C in this context has not previously been elucidated. Here we report that in Caki-1 tumor cells, protein kinase C α is a part of the transcription complex. With importin α4 and α5 as chaperones, the transcription complex transmigrates into the nucleus. Protein kinase C α blocks the nuclear release of pri-microRNA 15a by direct binding shown by electrophoretic mobility shift assay and Duolink immune histology. The expression levels of miRNA 15a can be further manipulated by transfection of si-protein kinase C α, or an expression vector containing protein kinase C α or miRNA 15. The miRNA 15a regulation by protein kinase C α is detectable in different malignant human tumor cell lines (renal cell carcinoma, breast carcinoma, and melanoma). Furthermore, all three cell lines harbor both endothelin receptors (ETAR/ETBR). Specific blockage of each receptor leads to major reduction of miRNA 15a expression due to increased nuclear protein kinase C α translocation. We conclude that the nuclear binding of pri-microRNA 15a is a novel function of protein kinase C α, which plays an important role in endothelin-1 mediated signaling. Since several endothelin-sensitive, malignant tumor cell lines harbor this regulation, it could indicate a more general role in tumor biology.

Original language	English
Journal	Biochimica et Biophysica Acta - Molecular Cell Research
Volume	1813
Issue number	10
Pages (from-to)	1793-1802
Number of pages	10
ISSN	0167-4889
DOIs	https://doi.org/10.1016/j.bbamcr.2011.06.006
Publication status	Published - 10.2011

Funding

We gratefully acknowledge helpful discussion for the design of the RNA-immunoprecipitation experiment by Dr. M. Montesinos-Rongen. The study was supported by a Köln Fortune post-doctoral fellowship and a grant from the 2nd Professorinenprogramm (to MvB), by a grant from the Deutsche Forschungsgemeinschaft DFG (to RD), by a grant from the Marga and Walter Boll Stiftung , Imhoff Stiftung , and the Nolting Stiftung (to JWUF). Since human cells were used, procedures have been followed as outlined in accordance with ethical standards as formulated in the Helsinki Declaration of 1975 (revised 1983). The use of patient tumor samples was approved by the University of Koeln Research Ethics Committee.

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Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)

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@article{da4a978e8eae48729c7cdf2660c7ad07,

title = "Protein kinase C α regulates nuclear pri-microRNA 15a release as part of endothelin signaling",

abstract = "Endothelin-1 induced signaling is characterized by an early induction of a nuclear factor-kappa B p65/mitogen-activated phosphokinase p38 transcription complex via its A-receptor versus a late induction via diacylglycerol, and protein kinase C. A possible interaction between these two pathways and a potential function for protein kinase C in this context has not previously been elucidated. Here we report that in Caki-1 tumor cells, protein kinase C α is a part of the transcription complex. With importin α4 and α5 as chaperones, the transcription complex transmigrates into the nucleus. Protein kinase C α blocks the nuclear release of pri-microRNA 15a by direct binding shown by electrophoretic mobility shift assay and Duolink immune histology. The expression levels of miRNA 15a can be further manipulated by transfection of si-protein kinase C α, or an expression vector containing protein kinase C α or miRNA 15. The miRNA 15a regulation by protein kinase C α is detectable in different malignant human tumor cell lines (renal cell carcinoma, breast carcinoma, and melanoma). Furthermore, all three cell lines harbor both endothelin receptors (ETAR/ETBR). Specific blockage of each receptor leads to major reduction of miRNA 15a expression due to increased nuclear protein kinase C α translocation. We conclude that the nuclear binding of pri-microRNA 15a is a novel function of protein kinase C α, which plays an important role in endothelin-1 mediated signaling. Since several endothelin-sensitive, malignant tumor cell lines harbor this regulation, it could indicate a more general role in tumor biology.",

author = "\{Von Brandenstein\}, Melanie and Reinhard Depping and Ekaterine Sch{\"a}fer and Dienes, \{Hans Peter\} and Fries, \{Jochen W.U.\}",

note = "Funding Information: We gratefully acknowledge helpful discussion for the design of the RNA-immunoprecipitation experiment by Dr. M. Montesinos-Rongen. The study was supported by a K{\"o}ln Fortune post-doctoral fellowship and a grant from the 2nd Professorinenprogramm (to MvB), by a grant from the Deutsche Forschungsgemeinschaft DFG (to RD), by a grant from the Marga and Walter Boll Stiftung , Imhoff Stiftung , and the Nolting Stiftung (to JWUF). Since human cells were used, procedures have been followed as outlined in accordance with ethical standards as formulated in the Helsinki Declaration of 1975 (revised 1983). The use of patient tumor samples was approved by the University of Koeln Research Ethics Committee. Copyright: Copyright 2011 Elsevier B.V., All rights reserved.",

year = "2011",

month = oct,

doi = "10.1016/j.bbamcr.2011.06.006",

language = "English",

volume = "1813",

pages = "1793--1802",

journal = "Biochimica et Biophysica Acta - Molecular Cell Research",

issn = "0167-4889",

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T1 - Protein kinase C α regulates nuclear pri-microRNA 15a release as part of endothelin signaling

AU - Von Brandenstein, Melanie

AU - Depping, Reinhard

AU - Schäfer, Ekaterine

AU - Dienes, Hans Peter

AU - Fries, Jochen W.U.

N1 - Funding Information: We gratefully acknowledge helpful discussion for the design of the RNA-immunoprecipitation experiment by Dr. M. Montesinos-Rongen. The study was supported by a Köln Fortune post-doctoral fellowship and a grant from the 2nd Professorinenprogramm (to MvB), by a grant from the Deutsche Forschungsgemeinschaft DFG (to RD), by a grant from the Marga and Walter Boll Stiftung , Imhoff Stiftung , and the Nolting Stiftung (to JWUF). Since human cells were used, procedures have been followed as outlined in accordance with ethical standards as formulated in the Helsinki Declaration of 1975 (revised 1983). The use of patient tumor samples was approved by the University of Koeln Research Ethics Committee. Copyright: Copyright 2011 Elsevier B.V., All rights reserved.

PY - 2011/10

Y1 - 2011/10

N2 - Endothelin-1 induced signaling is characterized by an early induction of a nuclear factor-kappa B p65/mitogen-activated phosphokinase p38 transcription complex via its A-receptor versus a late induction via diacylglycerol, and protein kinase C. A possible interaction between these two pathways and a potential function for protein kinase C in this context has not previously been elucidated. Here we report that in Caki-1 tumor cells, protein kinase C α is a part of the transcription complex. With importin α4 and α5 as chaperones, the transcription complex transmigrates into the nucleus. Protein kinase C α blocks the nuclear release of pri-microRNA 15a by direct binding shown by electrophoretic mobility shift assay and Duolink immune histology. The expression levels of miRNA 15a can be further manipulated by transfection of si-protein kinase C α, or an expression vector containing protein kinase C α or miRNA 15. The miRNA 15a regulation by protein kinase C α is detectable in different malignant human tumor cell lines (renal cell carcinoma, breast carcinoma, and melanoma). Furthermore, all three cell lines harbor both endothelin receptors (ETAR/ETBR). Specific blockage of each receptor leads to major reduction of miRNA 15a expression due to increased nuclear protein kinase C α translocation. We conclude that the nuclear binding of pri-microRNA 15a is a novel function of protein kinase C α, which plays an important role in endothelin-1 mediated signaling. Since several endothelin-sensitive, malignant tumor cell lines harbor this regulation, it could indicate a more general role in tumor biology.

AB - Endothelin-1 induced signaling is characterized by an early induction of a nuclear factor-kappa B p65/mitogen-activated phosphokinase p38 transcription complex via its A-receptor versus a late induction via diacylglycerol, and protein kinase C. A possible interaction between these two pathways and a potential function for protein kinase C in this context has not previously been elucidated. Here we report that in Caki-1 tumor cells, protein kinase C α is a part of the transcription complex. With importin α4 and α5 as chaperones, the transcription complex transmigrates into the nucleus. Protein kinase C α blocks the nuclear release of pri-microRNA 15a by direct binding shown by electrophoretic mobility shift assay and Duolink immune histology. The expression levels of miRNA 15a can be further manipulated by transfection of si-protein kinase C α, or an expression vector containing protein kinase C α or miRNA 15. The miRNA 15a regulation by protein kinase C α is detectable in different malignant human tumor cell lines (renal cell carcinoma, breast carcinoma, and melanoma). Furthermore, all three cell lines harbor both endothelin receptors (ETAR/ETBR). Specific blockage of each receptor leads to major reduction of miRNA 15a expression due to increased nuclear protein kinase C α translocation. We conclude that the nuclear binding of pri-microRNA 15a is a novel function of protein kinase C α, which plays an important role in endothelin-1 mediated signaling. Since several endothelin-sensitive, malignant tumor cell lines harbor this regulation, it could indicate a more general role in tumor biology.

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DO - 10.1016/j.bbamcr.2011.06.006

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AN - SCOPUS:80051791985

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JO - Biochimica et Biophysica Acta - Molecular Cell Research

JF - Biochimica et Biophysica Acta - Molecular Cell Research

IS - 10

ER -

Protein kinase C α regulates nuclear pri-microRNA 15a release as part of endothelin signaling

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