Regulation of Androgen Receptor Activity by Transient Interactions of Its Transactivation Domain with General Transcription Regulators

Eva De Mol; Elzbieta Szulc; Claudio Di Sanza; Paula Martínez-Cristóbal; Carlos W Bertoncini; R Bryn Fenwick; Marta Frigolé-Vivas; Marianela Masín; Irene Hunter; Víctor Buzón; Isabelle Brun-Heath; Jesús García; Gianni De Fabritiis; Eva Estébanez-Perpiñá; Iain J McEwan; Ángel R Nebreda; Xavier Salvatella

doi:10.1016/j.str.2017.11.007

Regulation of Androgen Receptor Activity by Transient Interactions of Its Transactivation Domain with General Transcription Regulators

Eva De Mol, Elzbieta Szulc, Claudio Di Sanza, Paula Martínez-Cristóbal, Carlos W Bertoncini, R Bryn Fenwick, Marta Frigolé-Vivas, Marianela Masín, Irene Hunter, Víctor Buzón, Isabelle Brun-Heath, Jesús García, Gianni De Fabritiis, Eva Estébanez-Perpiñá, Iain J McEwan, Ángel R Nebreda, Xavier Salvatella

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Abstract

The androgen receptor is a transcription factor that plays a key role in the development of prostate cancer, and its interactions with general transcription regulators are therefore of potential therapeutic interest. The mechanistic basis of these interactions is poorly understood due to the intrinsically disordered nature of the transactivation domain of the androgen receptor and the generally transient nature of the protein-protein interactions that trigger transcription. Here, we identify a motif of the transactivation domain that contributes to transcriptional activity by recruiting the C-terminal domain of subunit 1 of the general transcription regulator TFIIF. These findings provide molecular insights into the regulation of androgen receptor function and suggest strategies for treating castration-resistant prostate cancer.

Original language	English
Pages (from-to)	145-152
Number of pages	8
Journal	Structure
Volume	26
Issue number	1
Early online date	7 Dec 2017
DOIs	https://doi.org/10.1016/j.str.2017.11.007
Publication status	Published - 2 Jan 2018

Bibliographical note

Acknowledgments
The authors thank Miquel Pons, Philipp Selenko, and Peter Wright for helpful discussions as well as Joan Miquel Valverde (IRB) and the ICTS NMR facility, managed by the scientific and technological centers of the University of Barcelona (CCiT UB), for their help in protein production and NMR. They also thank the IRB protein expression core facility for its assistance in cloning, the IRB advanced microscopy facility for assistance in immunofluorescence and PLA, and the IRB biostatistics and bioinformatics facility for assistance in the analysis of the gene reporter and PLA data. This work was supported by IRB, ICREA (X.S.), Obra Social “la Caixa” (E.D.M., E.S., and X.S.), MINECO (BIO2012-31043 and BIO2015-70092-R to X.S., BIO2014-53095-P to G.D.F.), Marató de TV3 (102030 to X.S. and 102031 to E.E.-P), the COFUND program of the European Commission (C.D.S.), the European Research Council (CONCERT, contract number 648201 to X.S.), the Ramón y Cajal program of MICINN (RYC-2011-07873 to C.W.B.), the Serra Hunter Program (E.E.-P.), AGAUR (SGR-2014-56RR14 to E.E.-P), and FEDER (G.D.F.). I.H. was supported by funding from the Chief Scientist's Office of the Scottish Government (ETM-258, ETM-382). IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO (Government of Spain).

Keywords

androgen receptor
castration-resistant prostate cancer
transcription
intrinsic disorder
protein-protein interactions
transcription factor IIF
protein phosphorylation

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Iain McEwan
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De Mol, E., Szulc, E., Di Sanza, C., Martínez-Cristóbal, P., Bertoncini, C. W., Fenwick, R. B., Frigolé-Vivas, M., Masín, M., Hunter, I., Buzón, V., Brun-Heath, I., García, J., De Fabritiis, G., Estébanez-Perpiñá, E., McEwan, I. J., Nebreda, Á. R., & Salvatella, X. (2018). Regulation of Androgen Receptor Activity by Transient Interactions of Its Transactivation Domain with General Transcription Regulators. Structure, 26(1), 145-152. https://doi.org/10.1016/j.str.2017.11.007

De Mol, E, Szulc, E, Di Sanza, C, Martínez-Cristóbal, P, Bertoncini, CW, Fenwick, RB, Frigolé-Vivas, M, Masín, M, Hunter, I, Buzón, V, Brun-Heath, I, García, J, De Fabritiis, G, Estébanez-Perpiñá, E, McEwan, IJ, Nebreda, ÁR & Salvatella, X 2018, 'Regulation of Androgen Receptor Activity by Transient Interactions of Its Transactivation Domain with General Transcription Regulators', Structure, vol. 26, no. 1, pp. 145-152. https://doi.org/10.1016/j.str.2017.11.007

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abstract = "The androgen receptor is a transcription factor that plays a key role in the development of prostate cancer, and its interactions with general transcription regulators are therefore of potential therapeutic interest. The mechanistic basis of these interactions is poorly understood due to the intrinsically disordered nature of the transactivation domain of the androgen receptor and the generally transient nature of the protein-protein interactions that trigger transcription. Here, we identify a motif of the transactivation domain that contributes to transcriptional activity by recruiting the C-terminal domain of subunit 1 of the general transcription regulator TFIIF. These findings provide molecular insights into the regulation of androgen receptor function and suggest strategies for treating castration-resistant prostate cancer.",

keywords = "androgen receptor, castration-resistant prostate cancer, transcription, intrinsic disorder, protein-protein interactions, transcription factor IIF, protein phosphorylation",

author = "{De Mol}, Eva and Elzbieta Szulc and {Di Sanza}, Claudio and Paula Mart{\'i}nez-Crist{\'o}bal and Bertoncini, {Carlos W} and Fenwick, {R Bryn} and Marta Frigol{\'e}-Vivas and Marianela Mas{\'i}n and Irene Hunter and V{\'i}ctor Buz{\'o}n and Isabelle Brun-Heath and Jes{\'u}s Garc{\'i}a and {De Fabritiis}, Gianni and Eva Est{\'e}banez-Perpi{\~n}{\'a} and McEwan, {Iain J} and Nebreda, {{\'A}ngel R} and Xavier Salvatella",

note = "Acknowledgments The authors thank Miquel Pons, Philipp Selenko, and Peter Wright for helpful discussions as well as Joan Miquel Valverde (IRB) and the ICTS NMR facility, managed by the scientific and technological centers of the University of Barcelona (CCiT UB), for their help in protein production and NMR. They also thank the IRB protein expression core facility for its assistance in cloning, the IRB advanced microscopy facility for assistance in immunofluorescence and PLA, and the IRB biostatistics and bioinformatics facility for assistance in the analysis of the gene reporter and PLA data. This work was supported by IRB, ICREA (X.S.), Obra Social “la Caixa” (E.D.M., E.S., and X.S.), MINECO (BIO2012-31043 and BIO2015-70092-R to X.S., BIO2014-53095-P to G.D.F.), Marat{\'o} de TV3 (102030 to X.S. and 102031 to E.E.-P), the COFUND program of the European Commission (C.D.S.), the European Research Council (CONCERT, contract number 648201 to X.S.), the Ram{\'o}n y Cajal program of MICINN (RYC-2011-07873 to C.W.B.), the Serra Hunter Program (E.E.-P.), AGAUR (SGR-2014-56RR14 to E.E.-P), and FEDER (G.D.F.). I.H. was supported by funding from the Chief Scientist's Office of the Scottish Government (ETM-258, ETM-382). IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO (Government of Spain).",

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doi = "10.1016/j.str.2017.11.007",

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T1 - Regulation of Androgen Receptor Activity by Transient Interactions of Its Transactivation Domain with General Transcription Regulators

AU - De Mol, Eva

AU - Szulc, Elzbieta

AU - Di Sanza, Claudio

AU - Martínez-Cristóbal, Paula

AU - Bertoncini, Carlos W

AU - Fenwick, R Bryn

AU - Frigolé-Vivas, Marta

AU - Masín, Marianela

AU - Hunter, Irene

AU - Buzón, Víctor

AU - Brun-Heath, Isabelle

AU - García, Jesús

AU - De Fabritiis, Gianni

AU - Estébanez-Perpiñá, Eva

AU - McEwan, Iain J

AU - Nebreda, Ángel R

AU - Salvatella, Xavier

N1 - Acknowledgments The authors thank Miquel Pons, Philipp Selenko, and Peter Wright for helpful discussions as well as Joan Miquel Valverde (IRB) and the ICTS NMR facility, managed by the scientific and technological centers of the University of Barcelona (CCiT UB), for their help in protein production and NMR. They also thank the IRB protein expression core facility for its assistance in cloning, the IRB advanced microscopy facility for assistance in immunofluorescence and PLA, and the IRB biostatistics and bioinformatics facility for assistance in the analysis of the gene reporter and PLA data. This work was supported by IRB, ICREA (X.S.), Obra Social “la Caixa” (E.D.M., E.S., and X.S.), MINECO (BIO2012-31043 and BIO2015-70092-R to X.S., BIO2014-53095-P to G.D.F.), Marató de TV3 (102030 to X.S. and 102031 to E.E.-P), the COFUND program of the European Commission (C.D.S.), the European Research Council (CONCERT, contract number 648201 to X.S.), the Ramón y Cajal program of MICINN (RYC-2011-07873 to C.W.B.), the Serra Hunter Program (E.E.-P.), AGAUR (SGR-2014-56RR14 to E.E.-P), and FEDER (G.D.F.). I.H. was supported by funding from the Chief Scientist's Office of the Scottish Government (ETM-258, ETM-382). IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO (Government of Spain).

PY - 2018/1/2

Y1 - 2018/1/2

N2 - The androgen receptor is a transcription factor that plays a key role in the development of prostate cancer, and its interactions with general transcription regulators are therefore of potential therapeutic interest. The mechanistic basis of these interactions is poorly understood due to the intrinsically disordered nature of the transactivation domain of the androgen receptor and the generally transient nature of the protein-protein interactions that trigger transcription. Here, we identify a motif of the transactivation domain that contributes to transcriptional activity by recruiting the C-terminal domain of subunit 1 of the general transcription regulator TFIIF. These findings provide molecular insights into the regulation of androgen receptor function and suggest strategies for treating castration-resistant prostate cancer.

AB - The androgen receptor is a transcription factor that plays a key role in the development of prostate cancer, and its interactions with general transcription regulators are therefore of potential therapeutic interest. The mechanistic basis of these interactions is poorly understood due to the intrinsically disordered nature of the transactivation domain of the androgen receptor and the generally transient nature of the protein-protein interactions that trigger transcription. Here, we identify a motif of the transactivation domain that contributes to transcriptional activity by recruiting the C-terminal domain of subunit 1 of the general transcription regulator TFIIF. These findings provide molecular insights into the regulation of androgen receptor function and suggest strategies for treating castration-resistant prostate cancer.

KW - androgen receptor

KW - castration-resistant prostate cancer

KW - transcription

KW - intrinsic disorder

KW - protein-protein interactions

KW - transcription factor IIF

KW - protein phosphorylation

U2 - 10.1016/j.str.2017.11.007

DO - 10.1016/j.str.2017.11.007

M3 - Article

C2 - 29225078

SN - 0969-2126

VL - 26

SP - 145

EP - 152

JO - Structure

JF - Structure

IS - 1

ER -

Regulation of Androgen Receptor Activity by Transient Interactions of Its Transactivation Domain with General Transcription Regulators

Abstract

Bibliographical note

Keywords

UN SDGs

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Iain McEwan

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