This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental material
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Amazit, L.
Right arrow Articles by Mancini, M. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Amazit, L.
Right arrow Articles by Mancini, M. A.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, October 2007, p. 6913-6932, Vol. 27, No. 19
0270-7306/07/$08.00+0     doi:10.1128/MCB.01695-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Regulation of SRC-3 Intercompartmental Dynamics by Estrogen Receptor and Phosphorylation{triangledown} ,{dagger}

Larbi Amazit,1,2 Luigi Pasini,1 Adam T. Szafran,1 Valeria Berno,1,{ddagger} Ray-Chang Wu,1 Marylin Mielke,1 Elizabeth D. Jones,1 Maureen G. Mancini,1 Cruz A. Hinojos,1 Bert W. O'Malley,1 and Michael A. Mancini1*

Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030,1 INSERM 693, Récepteurs Stéroïdiens, Physiopathologie Endocrinienne et Métabolique, Faculte de Medecine Paris Sud, 63 rue Gabriel Peri, 94276 Le Kremlin Bicetre Cedex, France2

Received 9 September 2006/ Returned for modification 19 October 2006/ Accepted 23 May 2007

The steroid receptor coactivator 3 gene (SRC-3) (AIB1/ACTR/pCIP/RAC3/TRAM1) is a p160 family transcription coactivator and a known oncogene. Despite its importance, the functional regulation of SRC-3 remains poorly understood within a cellular context. Using a novel combination of live-cell, high-throughput, and fluorescent microscopy, we report SRC-3 to be a nucleocytoplasmic shuttling protein whose intracellular mobility, solubility, and cellular localization are regulated by phosphorylation and estrogen receptor {alpha} (ER{alpha}) interactions. We show that both chemical inhibition and small interfering RNA reduction of the mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (MEK1/2) pathway induce a cytoplasmic shift in SRC-3 localization, whereas stimulation by epidermal growth factor signaling enhances its nuclear localization by inducing phosphorylation at T24, S857, and S860, known participants in the phosphocode that regulates SRC-3 activity. Accordingly, the cytoplasmic localization of a nonphosphorylatable SRC-3 mutant further supported these results. In the presence of ER{alpha}, U0126 also dramatically reduces (i) ligand-dependent colocalization of SRC-3 and ER{alpha}, (ii) the formation of ER-SRC-3 complexes in cell lysates, and (iii) SRC-3 targeting to a visible, ER{alpha}-occupied and -regulated prolactin promoter array. Taken together, these results indicate that phosphorylation coordinates SRC-3 coactivator function by linking the probabilistic formation of transient nuclear receptor-coactivator complexes with its molecular dynamics and cellular compartmentalization. Technically and conceptually, these findings have a new and broad impact upon evaluating mechanisms of action of gene regulators at a cellular system level.

* Corresponding author. Mailing address: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030. Phone: (713) 798-8952. Fax: (713) 798-3175. E-mail: mancini{at}bcm.edu

{triangledown} Published ahead of print on 23 July 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: European Molecular Biology Laboratory, Mouse Biology Unit, 00016 Monterotondo, Italy.

Molecular and Cellular Biology, October 2007, p. 6913-6932, Vol. 27, No. 19
0270-7306/07/$08.00+0     doi:10.1128/MCB.01695-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Giamas, G., Castellano, L., Feng, Q., Knippschild, U., Jacob, J., Thomas, R. S., Coombes, R. C., Smith, C. L., Jiao, L. R., Stebbing, J. (2009). CK1{delta} modulates the transcriptional activity of ER{alpha} via AIB1 in an estrogen-dependent manner and regulates ER{alpha}-AIB1 interactions. Nucleic Acids Res 37: 3110-3123 [Abstract] [Full Text]  
  • Redmond, A. M., Bane, F. T., Stafford, A. T., McIlroy, M., Dillon, M. F., Crotty, T. B., Hill, A. D., Young, L. S. (2009). Coassociation of Estrogen Receptor and p160 Proteins Predicts Resistance to Endocrine Treatment; SRC-1 is an Independent Predictor of Breast Cancer Recurrence. Clin. Cancer Res. 15: 2098-2106 [Abstract] [Full Text]  
  • Oh, A. S., Lahusen, J. T., Chien, C. D., Fereshteh, M. P., Zhang, X., Dakshanamurthy, S., Xu, J., Kagan, B. L., Wellstein, A., Riegel, A. T. (2008). Tyrosine Phosphorylation of the Nuclear Receptor Coactivator AIB1/SRC-3 Is Enhanced by Abl Kinase and Is Required for Its Activity in Cancer Cells. Mol. Cell. Biol. 28: 6580-6593 [Abstract] [Full Text]  
  • Madak-Erdogan, Z., Kieser, K. J., Kim, S. H., Komm, B., Katzenellenbogen, J. A., Katzenellenbogen, B. S. (2008). Nuclear and Extranuclear Pathway Inputs in the Regulation of Global Gene Expression by Estrogen Receptors. Mol. Endocrinol. 22: 2116-2127 [Abstract] [Full Text]  
  • Ferrero, M., Avivar, A., Garcia-Macias, M. C., de Mora, J. F. (2008). Phosphoinositide 3-kinase/AKT Signaling Can Promote AIB1 Stability Independently of GSK3 Phosphorylation. Cancer Res. 68: 5450-5459 [Abstract] [Full Text]  


Copyright © 2010 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»