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

Journal Article · Tue May 15 00:00:00 EDT 2007 · Experimental Cell Research

DOI:https://doi.org/10.1016/j.yexcr.2007.03.008· OSTI ID:20972152

Hinton, Cimona V ^[1]; Fitzgerald, Latricia D ^[1]; Thompson, Marilyn E ^[2]

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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)

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.

• OSTI ID: 20972152
• Journal Information: Experimental Cell Research, Vol. 313, 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); ISSN 0014-4827
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ALANINES
CARCINOMAS
MAMMARY GLANDS
MUTATIONS
PHOSPHORYLATION
PROMOTERS
THREONINE