Transcription repressor activity of spleen tyrosine kinase mediates breast tumor suppression.

Spleen tyrosine kinase (SYK) is a candidate tumor suppressor gene in breast. Loss of SYK expression in breast tumors as a result of DNA hypermethylation promotes tumor cell proliferation and invasion and predicts shorter survival of breast cancer patients. We previously reported that, in addition to its well-known cytoplasmic localization, ...
the full-length Syk is also present in the nucleus and that Syk nuclear translocation is a rate-limiting step to determine Syk tumor suppressor function. Here, we show that the full-length form of Syk acts as a transcription repressor in the cell nucleus. Ectopic expression of Syk down-regulates the transcription of FRA1 and cyclin D1 oncogenes. This transcription-repressing activity of Syk is associated with its binding to members of the histone deacetylase family. Syk interacts with transcription factor Sp1 at the Sp1 DNA-binding site in the FRA1 promoter to repress Sp1-activated FRA1 transcription. Thus, breast tumorigenesis and progression resulting from the loss of SYK are underscored by the derepression of Sp1-mediated oncogene transcription.
Mesh Terms:
Animals, Breast Neoplasms, COS Cells, Cell Line, Tumor, Cercopithecus aethiops, Enzyme Precursors, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Histone Deacetylases, Humans, Intracellular Signaling Peptides and Proteins, Promoter Regions, Genetic, Protein-Tyrosine Kinases, Repressor Proteins, Transcriptional Activation
Cancer Res.
Date: Nov. 15, 2005
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