1. Atypical protein kinase C regulates dual pathways for degradation of the oncogenic coactivator SRC-3/AIB1.
- Author
-
Yi P, Feng Q, Amazit L, Lonard DM, Tsai SY, Tsai MJ, and O'Malley BW
- 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
- 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.
- Published
- 2008
- Full Text
- View/download PDF