N-terminal truncation of Stat5a/b circumvents PIAS3-mediated transcriptional inhibition of Stat5 in prostate cancer cells. Int J Biochem Cell Biol 2010 Dec;42(12):2037-46
Date
09/22/2010Pubmed ID
20854925Pubmed Central ID
PMC2982800DOI
10.1016/j.biocel.2010.09.008Scopus ID
2-s2.0-78149283094 (requires institutional sign-in at Scopus site) 20 CitationsAbstract
Transcription factor Stat5a/b is critical for prostate cancer cell survival and for prostate xenograft tumor growth. In addition, the Stat5a/b signaling pathway may contribute to progression of organ-confined prostate cancer to castration-resistant and/or metastatic disease. Expression of nuclear Stat5a/b is clustered to high grade human prostate cancers, and nuclear Stat5a/b in primary prostate cancer predicts early disease recurrence after initial treatment. Here, we show by Western blotting and electromobility shift assay that Stat5a/b protein in human prostate cancer is N-terminally truncated. This short form of Stat5a/b is generated post-translationally in vivo in prostate cancer cells and is the predominant form of Stat5a/b that binds to DNA. We further demonstrate by mutagenesis and co-immunoprecipitations that the N-domain of Stat5a/b is required for binding to PIAS3, and that PIAS3 inhibits transcriptional activity of Stat5a/b in breast cancer cells but not in prostate cancer cells. Thus, the proteolytic cleavage of the N-terminus of Stat5a/b may be a mechanism by which Stat5 evades the transcriptional repression by PIAS3 in prostate cancer cells, and results in increased Stat5-driven gene expression and prostate cancer progression.
Author List
Dagvadorj A, Tan SH, Liao Z, Xie J, Nurmi M, Alanen K, Rui H, Mirtti T, Nevalainen MTMESH terms used to index this publication - Major topics in bold
Cell Line, TumorCell Survival
Gene Expression Regulation, Neoplastic
Humans
Immunohistochemistry
Male
Molecular Chaperones
Prostatic Neoplasms
Protein Inhibitors of Activated STAT
STAT5 Transcription Factor
Transcription, Genetic
Tumor Suppressor Proteins
