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Molecular and Cellular Biology, February 2007, p. 1296-1308, Vol. 27, No. 4
0270-7306/07/$08.00+0     doi:10.1128/MCB.00336-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Specific Amino Acid Residues in the Basic Helix-Loop-Helix Domain of SRC-3 Are Essential for Its Nuclear Localization and Proteasome-Dependent Turnover{triangledown}

Chao Li, Ray-Chang Wu, Larbi Amazit, Sophia Y. Tsai, Ming-Jer Tsai, and Bert W. O'Malley*

Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030

Received 23 February 2006/ Returned for modification 26 April 2006/ Accepted 22 November 2006

SRC-3/AIB1/ACTR/pCIP/RAC3/TRAM-1 is a primary transcriptional coactivator for the estrogen receptor. Here we report that deletion of the SRC-3 basic helix-loop-helix (bHLH) domain blocks its proteasome-dependent turnover. We further identified two residues (K17 and R18) in the SRC-3 bHLH domain that are essential for its stability. Moreover, we found that the bHLH domain contains a bipartite nuclear localization signal (NLS). SRC-3 NLS mutants block its translocation into the nucleus, and this correlates with its insensitivity to proteasome-dependent turnover. SRC-3 shows a time-dependent decay in the presence of cycloheximide which is not apparent for the cytoplasmic mutant. Fusion of a simian virus 40 T antigen NLS to the cytoplasmic localized SRC-3 mutant drives it back into the nucleus and restores its proteasomal sensitivity. In addition, the cytoplasmic mutants are inactive for transcriptional coactivation and cancer cell growth. Taken together, our data indicate that proteasome-dependent turnover of SRC-3 occurs in the nucleus and that two amino acid residues in the bHLH domain provide a signal for its nuclear localization and proteasome-dependent degradation as well as for regulation of SRC-3 transcriptional coactivator capacity.

* Corresponding author. Mailing address: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Phone: (713) 798-6205. Fax: (713) 798-5599. E-mail: berto{at}bcm.tmc.edu.

{triangledown} Published ahead of print on 11 December 2006.

Molecular and Cellular Biology, February 2007, p. 1296-1308, Vol. 27, No. 4
0270-7306/07/$08.00+0     doi:10.1128/MCB.00336-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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