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Specific amino acid residues in the basic helix-loop-helix domain of SRC-3 are essential for its nuclear localization and proteasome-dependent turnover.
- Source :
-
Molecular and cellular biology [Mol Cell Biol] 2007 Feb; Vol. 27 (4), pp. 1296-308. Date of Electronic Publication: 2006 Dec 11. - Publication Year :
- 2007
-
Abstract
- 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.
- Subjects :
- Active Transport, Cell Nucleus
Amino Acid Sequence
Antigens, Polyomavirus Transforming metabolism
Cell Growth Processes
Cytoplasm metabolism
Genes, Reporter
HeLa Cells
Humans
Molecular Sequence Data
Mutant Proteins metabolism
Nuclear Localization Signals chemistry
Nuclear Receptor Coactivator 3
Protein Structure, Tertiary
Structure-Activity Relationship
Thermodynamics
Transcription, Genetic
Arginine metabolism
Cell Nucleus metabolism
Helix-Loop-Helix Motifs
Histone Acetyltransferases chemistry
Histone Acetyltransferases metabolism
Lysine metabolism
Proteasome Endopeptidase Complex metabolism
Trans-Activators chemistry
Trans-Activators metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0270-7306
- Volume :
- 27
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Molecular and cellular biology
- Publication Type :
- Academic Journal
- Accession number :
- 17158932
- Full Text :
- https://doi.org/10.1128/MCB.00336-06