AKT regulates BRCA1 stability in response to hormone signaling

Andrew C. Nelson; Traci R. Lyons; Christian D. Young; Kirk C. Hansen; Steven M. Anderson; Jeffrey T. Holt

doi:10.1016/j.mce.2010.01.019

AKT regulates BRCA1 stability in response to hormone signaling

Andrew C. Nelson, Traci R. Lyons, Christian D. Young, Kirk C. Hansen, Steven M. Anderson, Jeffrey T. Holt

Laboratory Medicine and Pathology

Research output: Contribution to journal › Article › peer-review

30 Scopus citations

Abstract

The observation that inherited mutations within BRCA1 result in breast and ovarian cancers suggests a functional relationship may exist between hormone signaling and BRCA1 function. We demonstrate that AKT activation promotes the expression of BRCA1 in response to estrogen and IGF-1 receptor signaling, and the rapid increase in BRCA1 protein levels appears to occur independently of new protein synthesis. Further, we identify a novel AKT phosphorylation site in BRCA1 at S694 which is responsive to activation of these signaling pathways. These data suggest AKT phosphorylation of BRCA1 increases total protein expression by preventing proteasomal degradation. AKT activation also appears to support nuclear localization of BRCA1, and co-expression of activated AKT with BRCA1 decreases radiation sensitivity, suggesting this interaction has functional consequences for BRCA1's role in DNA repair. Targets within this pathway could provide strategies for modulation of BRCA1 protein, which may prove therapeutically beneficial for breast and ovarian cancer treatment.

Original language	English (US)
Pages (from-to)	129-142
Number of pages	14
Journal	Molecular and Cellular Endocrinology
Volume	319
Issue number	1-2
DOIs	https://doi.org/10.1016/j.mce.2010.01.019
State	Published - May 5 2010

Bibliographical note

Funding Information:
This work was funded by grants from the Department of Defense Breast Cancer Research Program W81XWH-06-1-0335 to ACN, DAMD17-02-1-0351 to TRL, W81XWH-06-1-0423 to CDY, and from the Public Health Service DK063674 to SMA. The authors wish to thank: Ms. Maria Wong and Ms. Rita Lieberman for technical laboratory assistance, Ms. Lisa Litzenberger for preparation of the figures, Dr. Jerome Schaack for assistance with recombinant adenovirus production, Drs. David Orlicky and James McManaman for assistance with microscopy, Ms. Lauren Kiemele for assistance with mass spectroscopy, and Mr. Michael Rudolph and Dr. Wilbur Franklin for assistance with qPCR. Bortezomib was provided by Dr. Stuart Lind. The Proteomics and Flow Cytometry Core Laboratories at the University of Colorado Cancer Center contributed to this work. Appendix A

Keywords

AKT
BRCA1
Breast cancer
Estrogen
IGF1
Phosphorylation
Proteasome

UN SDGs

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

Access

10.1016/j.mce.2010.01.019

OpenUrl availability

Full text

Cite this

@article{29f905133b444a5eb338fa4d87410120,

title = "AKT regulates BRCA1 stability in response to hormone signaling",

abstract = "The observation that inherited mutations within BRCA1 result in breast and ovarian cancers suggests a functional relationship may exist between hormone signaling and BRCA1 function. We demonstrate that AKT activation promotes the expression of BRCA1 in response to estrogen and IGF-1 receptor signaling, and the rapid increase in BRCA1 protein levels appears to occur independently of new protein synthesis. Further, we identify a novel AKT phosphorylation site in BRCA1 at S694 which is responsive to activation of these signaling pathways. These data suggest AKT phosphorylation of BRCA1 increases total protein expression by preventing proteasomal degradation. AKT activation also appears to support nuclear localization of BRCA1, and co-expression of activated AKT with BRCA1 decreases radiation sensitivity, suggesting this interaction has functional consequences for BRCA1's role in DNA repair. Targets within this pathway could provide strategies for modulation of BRCA1 protein, which may prove therapeutically beneficial for breast and ovarian cancer treatment.",

keywords = "AKT, BRCA1, Breast cancer, Estrogen, IGF1, Phosphorylation, Proteasome",

author = "Nelson, {Andrew C.} and Lyons, {Traci R.} and Young, {Christian D.} and Hansen, {Kirk C.} and Anderson, {Steven M.} and Holt, {Jeffrey T.}",

note = "Funding Information: This work was funded by grants from the Department of Defense Breast Cancer Research Program W81XWH-06-1-0335 to ACN, DAMD17-02-1-0351 to TRL, W81XWH-06-1-0423 to CDY, and from the Public Health Service DK063674 to SMA. The authors wish to thank: Ms. Maria Wong and Ms. Rita Lieberman for technical laboratory assistance, Ms. Lisa Litzenberger for preparation of the figures, Dr. Jerome Schaack for assistance with recombinant adenovirus production, Drs. David Orlicky and James McManaman for assistance with microscopy, Ms. Lauren Kiemele for assistance with mass spectroscopy, and Mr. Michael Rudolph and Dr. Wilbur Franklin for assistance with qPCR. Bortezomib was provided by Dr. Stuart Lind. The Proteomics and Flow Cytometry Core Laboratories at the University of Colorado Cancer Center contributed to this work. Appendix A ",

year = "2010",

month = may,

day = "5",

doi = "10.1016/j.mce.2010.01.019",

language = "English (US)",

volume = "319",

pages = "129--142",

journal = "Molecular and Cellular Endocrinology",

issn = "0303-7207",

publisher = "Elsevier Ireland Ltd",

number = "1-2",

}

TY - JOUR

T1 - AKT regulates BRCA1 stability in response to hormone signaling

AU - Nelson, Andrew C.

AU - Lyons, Traci R.

AU - Young, Christian D.

AU - Hansen, Kirk C.

AU - Anderson, Steven M.

AU - Holt, Jeffrey T.

N1 - Funding Information: This work was funded by grants from the Department of Defense Breast Cancer Research Program W81XWH-06-1-0335 to ACN, DAMD17-02-1-0351 to TRL, W81XWH-06-1-0423 to CDY, and from the Public Health Service DK063674 to SMA. The authors wish to thank: Ms. Maria Wong and Ms. Rita Lieberman for technical laboratory assistance, Ms. Lisa Litzenberger for preparation of the figures, Dr. Jerome Schaack for assistance with recombinant adenovirus production, Drs. David Orlicky and James McManaman for assistance with microscopy, Ms. Lauren Kiemele for assistance with mass spectroscopy, and Mr. Michael Rudolph and Dr. Wilbur Franklin for assistance with qPCR. Bortezomib was provided by Dr. Stuart Lind. The Proteomics and Flow Cytometry Core Laboratories at the University of Colorado Cancer Center contributed to this work. Appendix A

PY - 2010/5/5

Y1 - 2010/5/5

N2 - The observation that inherited mutations within BRCA1 result in breast and ovarian cancers suggests a functional relationship may exist between hormone signaling and BRCA1 function. We demonstrate that AKT activation promotes the expression of BRCA1 in response to estrogen and IGF-1 receptor signaling, and the rapid increase in BRCA1 protein levels appears to occur independently of new protein synthesis. Further, we identify a novel AKT phosphorylation site in BRCA1 at S694 which is responsive to activation of these signaling pathways. These data suggest AKT phosphorylation of BRCA1 increases total protein expression by preventing proteasomal degradation. AKT activation also appears to support nuclear localization of BRCA1, and co-expression of activated AKT with BRCA1 decreases radiation sensitivity, suggesting this interaction has functional consequences for BRCA1's role in DNA repair. Targets within this pathway could provide strategies for modulation of BRCA1 protein, which may prove therapeutically beneficial for breast and ovarian cancer treatment.

AB - The observation that inherited mutations within BRCA1 result in breast and ovarian cancers suggests a functional relationship may exist between hormone signaling and BRCA1 function. We demonstrate that AKT activation promotes the expression of BRCA1 in response to estrogen and IGF-1 receptor signaling, and the rapid increase in BRCA1 protein levels appears to occur independently of new protein synthesis. Further, we identify a novel AKT phosphorylation site in BRCA1 at S694 which is responsive to activation of these signaling pathways. These data suggest AKT phosphorylation of BRCA1 increases total protein expression by preventing proteasomal degradation. AKT activation also appears to support nuclear localization of BRCA1, and co-expression of activated AKT with BRCA1 decreases radiation sensitivity, suggesting this interaction has functional consequences for BRCA1's role in DNA repair. Targets within this pathway could provide strategies for modulation of BRCA1 protein, which may prove therapeutically beneficial for breast and ovarian cancer treatment.

KW - AKT

KW - BRCA1

KW - Breast cancer

KW - Estrogen

KW - IGF1

KW - Phosphorylation

KW - Proteasome

UR - http://www.scopus.com/inward/record.url?scp=77249087580&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77249087580&partnerID=8YFLogxK

U2 - 10.1016/j.mce.2010.01.019

DO - 10.1016/j.mce.2010.01.019

M3 - Article

C2 - 20085797

AN - SCOPUS:77249087580

SN - 0303-7207

VL - 319

SP - 129

EP - 142

JO - Molecular and Cellular Endocrinology

JF - Molecular and Cellular Endocrinology

IS - 1-2

ER -

AKT regulates BRCA1 stability in response to hormone signaling

Abstract

Bibliographical note

Keywords

UN SDGs

Access

OpenUrl availability

Other files and links

Fingerprint

Cite this