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Atypical protein kinase C regulates dual pathways for degradation of the oncogenic coactivator SRC-3/AIB1.
- Source :
-
Molecular cell [Mol Cell] 2008 Feb 29; Vol. 29 (4), pp. 465-76. - Publication Year :
- 2008
-
Abstract
- SRC-3/AIB1 is a steroid receptor coactivator with potent growth-promoting activity, and its overexpression is sufficient to induce tumorigenesis. Previous studies indicate that the cellular level of SRC-3 is tightly regulated by both ubiquitin-dependent and ubiquitin-independent proteasomal degradation pathways. Atypical protein kinase C (aPKC) is frequently overexpressed in cancers. In the present study, we show that aPKC phosphorylates and specifically stabilizes SRC-3 in a selective ER-dependent manner. We further demonstrate that an acidic residue-rich region in SRC-3 is an important determinant for aPKC-mediated phosphorylation and stabilization. The mechanism of the aPKC-mediated stabilization appears due to a decreased interaction between SRC-3 and the C8 subunit of the 20S core proteasome, thus preventing SRC-3 degradation. Our results demonstrate a potent signaling mechanism for regulating SRC-3 levels in cells by coordinate enzymatic inhibition of both ubiquitin-dependent and ubiquitin-independent proteolytic pathways.
- Subjects :
- Amino Acid Sequence
Animals
Breast Neoplasms metabolism
Cell Line
Endoplasmic Reticulum metabolism
Estrogen Receptor alpha genetics
Estrogen Receptor alpha metabolism
Estrogens metabolism
Female
Gene Expression Regulation
Histone Acetyltransferases chemistry
Histone Acetyltransferases genetics
Humans
Isoenzymes genetics
Mice
Molecular Sequence Data
Nuclear Receptor Coactivator 3
Phosphorylation
Proteasome Endopeptidase Complex metabolism
Protein Kinase C genetics
Protein Subunits genetics
Protein Subunits metabolism
Sequence Alignment
Trans-Activators chemistry
Trans-Activators genetics
Transcription Factors genetics
Histone Acetyltransferases metabolism
Isoenzymes metabolism
Protein Kinase C metabolism
Trans-Activators metabolism
Transcription Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4164
- Volume :
- 29
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Molecular cell
- Publication Type :
- Academic Journal
- Accession number :
- 18313384
- Full Text :
- https://doi.org/10.1016/j.molcel.2007.12.030