ZIP: a novel transcription repressor, represses EGFR oncogene and suppresses breast carcinogenesis.
ABSTRACT Despite the importance of epidermal growth factor receptor (EGFR) in animal development and malignant transformation, surprisingly little is known about the regulation of its expression. Here, we report a novel zinc finger and G-patch domain-containing protein, ZIP. We demonstrated that ZIP acts as a transcription repressor through the recruitment of the nucleosome remodelling and deacetylase complex. Transcriptional target analysis revealed that ZIP regulates several cellular signalling pathways including EGFR pathways that are critically involved in cell proliferation, survival, and migration. We showed that ZIP inhibits cell proliferation and suppresses breast carcinogenesis, and that ZIP depletion leads to a drastic tumour growth in vivo. We found that ZIP is downregulated in breast carcinomas and that its level of expression is negatively correlated with that of EGFR. Our data indicate that ZIP is a novel transcription repressor and a potential tumour suppressor. These findings may shed new light on the EGFR-related breast carcinogenesis and might offer a potential new target for breast cancer therapy.
Article: G-patch domain and KOW motifs-containing protein, GPKOW; a nuclear RNA-binding protein regulated by protein kinase A.[show abstract] [hide abstract]
ABSTRACT: ABSTRACT: Post-transcriptional processing of pre-mRNA takes place in several steps and requires involvement of a number of RNA-binding proteins. How pre-mRNA processing is regulated is in large enigmatic. The catalytic (C) subunit of protein kinase A (PKA) is a serine/threonine kinase, which regulates numerous cellular processes including pre-mRNA splicing. Despite that a significant fraction of the C subunit is found in splicing factor compartments in the nucleus, there are no indications of a direct interaction between RNA and PKA. Based on this we speculate if the specificity of the C subunit in regulating pre-mRNA splicing may be mediated indirectly through other nuclear proteins. Using yeast two-hybrid screening with the PKA C subunit Cbeta2 as bait, we identified the G-patch domain and KOW motifs-containing protein (GPKOW), also known as the T54 protein or MOS2 homolog, as an interaction partner for Cbeta2. We demonstrate that GPKOW, which contains one G-patch domain and two KOW motifs, is a nuclear RNA-binding protein conserved between species. GPKOW contains two sites that are phosphorylated by PKA in vitro. By RNA immunoprecipitation and site directed mutagenesis of the PKA phosphorylation sites we revealed that GPKOW binds RNA in vivo in a PKA sensitive fashion. GPKOW is a RNA-binding protein that binds RNA in a PKA regulated fashion. Together with our previous results demonstrating that PKA regulates pre-mRNA splicing, our results suggest that PKA phosphorylation is involved in regulating RNA processing at several steps.Journal of Molecular Signaling 08/2011; 6:10.