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Title: Phosphatidylinositol 3-kinase/Akt signaling enhances nuclear localization and transcriptional activity of BRCA1

Abstract

Signaling pathways involved in regulating nuclear-cytoplasmic distribution of BRCA1 have not been previously reported. Here, we provide evidence that heregulin {beta}1-induced activation of the Akt pathway increases the nuclear content of BRCA1. First, treatment of T47D breast cancer cells with heregulin {beta}1 results in a two-fold increase in nuclear BRCA1 as assessed by FACS analysis, immunoblotting and immunofluorescence. This heregulin-induced increase in nuclear BRCA1 is blocked by siRNA-mediated down-regulation of Akt. Second, mutation of threonine 509 in BRCA1, the site of Akt phosphorylation, to an alanine, attenuates the ability of heregulin to induce BRCA1 nuclear accumulation. These data suggest that Akt-catalyzed phosphorylation of BRCA1 is required for the heregulin-regulated nuclear concentration of BRCA1. Because most functions ascribed to BRCA1 occur within the nucleus, we postulated that phosphorylation-dependent nuclear accumulation of BRCA1 would result in enhanced nuclear activity, specifically transcriptional activity, of BRCA1. This postulate is affirmed by our observation that the ability of BRCA1 to transactivate GADD45 promoter constructs was enhanced in T47D cells treated with heregulin {beta}1. Furthermore, the heterologous expression of BRCA1 in HCC1937 human breast cancer cells, which have constitutively active Akt, also induces GADD45 promoter activity, whereas the expression of BRCA1 in which threonine 509 hasmore » been mutated to an alanine is able to only minimally induce promoter activity. These findings implicate Akt in upstream events leading to BRCA1 nuclear localization and function.« less

Authors:
 [1];  [1];  [2]
  1. Division of Cancer Biology, Meharry Medical College, WBSC 2137, 1005 D.B. Todd Blvd., Nashville, TN 37208-3599 (United States)
  2. Division of Cancer Biology, Meharry Medical College, WBSC 2137, 1005 D.B. Todd Blvd., Nashville, TN 37208-3599 (United States) and Vanderbilt-Ingram Cancer Center, Nashville, TN 37232 (United States). E-mail: methompson@mmc.edu
Publication Date:
OSTI Identifier:
20972152
Resource Type:
Journal Article
Resource Relation:
Journal Name: Experimental Cell Research; Journal Volume: 313; Journal Issue: 9; Other Information: DOI: 10.1016/j.yexcr.2007.03.008; PII: S0014-4827(07)00112-7; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ALANINES; CARCINOMAS; MAMMARY GLANDS; MUTATIONS; PHOSPHORYLATION; PROMOTERS; THREONINE

Citation Formats

Hinton, Cimona V., Fitzgerald, Latricia D., and Thompson, Marilyn E. Phosphatidylinositol 3-kinase/Akt signaling enhances nuclear localization and transcriptional activity of BRCA1. United States: N. p., 2007. Web. doi:10.1016/j.yexcr.2007.03.008.
Hinton, Cimona V., Fitzgerald, Latricia D., & Thompson, Marilyn E. Phosphatidylinositol 3-kinase/Akt signaling enhances nuclear localization and transcriptional activity of BRCA1. United States. doi:10.1016/j.yexcr.2007.03.008.
Hinton, Cimona V., Fitzgerald, Latricia D., and Thompson, Marilyn E. Tue . "Phosphatidylinositol 3-kinase/Akt signaling enhances nuclear localization and transcriptional activity of BRCA1". United States. doi:10.1016/j.yexcr.2007.03.008.
@article{osti_20972152,
title = {Phosphatidylinositol 3-kinase/Akt signaling enhances nuclear localization and transcriptional activity of BRCA1},
author = {Hinton, Cimona V. and Fitzgerald, Latricia D. and Thompson, Marilyn E.},
abstractNote = {Signaling pathways involved in regulating nuclear-cytoplasmic distribution of BRCA1 have not been previously reported. Here, we provide evidence that heregulin {beta}1-induced activation of the Akt pathway increases the nuclear content of BRCA1. First, treatment of T47D breast cancer cells with heregulin {beta}1 results in a two-fold increase in nuclear BRCA1 as assessed by FACS analysis, immunoblotting and immunofluorescence. This heregulin-induced increase in nuclear BRCA1 is blocked by siRNA-mediated down-regulation of Akt. Second, mutation of threonine 509 in BRCA1, the site of Akt phosphorylation, to an alanine, attenuates the ability of heregulin to induce BRCA1 nuclear accumulation. These data suggest that Akt-catalyzed phosphorylation of BRCA1 is required for the heregulin-regulated nuclear concentration of BRCA1. Because most functions ascribed to BRCA1 occur within the nucleus, we postulated that phosphorylation-dependent nuclear accumulation of BRCA1 would result in enhanced nuclear activity, specifically transcriptional activity, of BRCA1. This postulate is affirmed by our observation that the ability of BRCA1 to transactivate GADD45 promoter constructs was enhanced in T47D cells treated with heregulin {beta}1. Furthermore, the heterologous expression of BRCA1 in HCC1937 human breast cancer cells, which have constitutively active Akt, also induces GADD45 promoter activity, whereas the expression of BRCA1 in which threonine 509 has been mutated to an alanine is able to only minimally induce promoter activity. These findings implicate Akt in upstream events leading to BRCA1 nuclear localization and function.},
doi = {10.1016/j.yexcr.2007.03.008},
journal = {Experimental Cell Research},
number = 9,
volume = 313,
place = {United States},
year = {Tue May 15 00:00:00 EDT 2007},
month = {Tue May 15 00:00:00 EDT 2007}
}