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SZIP, an alternative splice variant of ZIP, antagonizes transcription repression and growth inhibition by ZIP.

ABSTRACT: Recently, we reported a novel transcriptional repressor, ZIP (for zinc finger and G-patch domain-containing), which recruits the Mi-2/NuRD (nucleosome remodeling and deacetylase) complex and represses the expression of epidermal growth factor receptor (EGFR). In doing so, ZIP inhibits cell proliferation and suppresses breast carcinogenesis. Here, we report the cloning and the characterization of an alternatively spliced isoform of ZIP, sZIP. sZIP is an N-terminal truncated form of ZIP, lacking the zinc finger but retaining part of the G-patch domain and C-terminal coiled-coil domain of ZIP. We showed that sZIP could interact with the NuRD complex but lost its DNA-binding capacity. We demonstrated that sZIP antagonizes the transcription repression by ZIP by competing for the binding of the NuRD complex and that sZIP alleviates the growth inhibitory effect of ZIP on hepatocarcinoma cells through attenuating the transcriptional repression of EGFR. Our data provide a finely tuned mechanism for EGFR regulation and add another player for transcription repression.

SUBMITTER: Yu W

PROVIDER: S-EPMC2863213 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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sZIP, an alternative splice variant of ZIP, antagonizes transcription repression and growth inhibition by ZIP.

Yu Wenhua W Li Ruifang R Gui Bin B Shang Yongfeng Y

The Journal of biological chemistry 20100316 19

Recently, we reported a novel transcriptional repressor, ZIP (for zinc finger and G-patch domain-containing), which recruits the Mi-2/NuRD (nucleosome remodeling and deacetylase) complex and represses the expression of epidermal growth factor receptor (EGFR). In doing so, ZIP inhibits cell proliferation and suppresses breast carcinogenesis. Here, we report the cloning and the characterization of an alternatively spliced isoform of ZIP, sZIP. sZIP is an N-terminal truncated form of ZIP, lacking t ...[more]

PMID: 20233718

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Project description:Protein tyrosine kinase 6 (PTK6), also called breast tumor kinase (BRK), is expressed in epithelial cells of various tissues including the prostate. Previously it was shown that PTK6 is localized to epithelial cell nuclei in normal prostate, but becomes cytoplasmic in human prostate tumors. PTK6 is also primarily cytoplasmic in the PC3 prostate adenocarcinoma cell line. Sequencing revealed expression of wild type full-length PTK6 transcripts in addition to an alternative transcript lacking exon 2 in PC3 cells. The alternative transcript encodes a 134 amino acid protein, referred to here as ALT-PTK6, which shares the first 77 amino acid residues including the SH3 domain with full length PTK6. RT-PCR was used to show that ALT-PTK6 is coexpressed with full length PTK6 in established human prostate and colon cell lines, as well as in primary cell lines derived from human prostate tissue and tumors. Although interaction between full-length PTK6 and ALT-PTK6 was not detected, ALT-PTK6 associates with the known PTK6 substrates Sam68 and β-catenin in GST pull-down assays. Coexpression of PTK6 and ALT-PTK6 led to suppression of PTK6 activity and reduced association of PTK6 with tyrosine phosphorylated proteins. While ALT-PTK6 alone did not influence β-catenin/TCF transcriptional activity in a luciferase reporter assay, it enhanced PTK6-mediated inhibition of β-catenin/TCF transcription by promoting PTK6 nuclear functions. Ectopic expression of ALT-PTK6 led to reduced expression of the β-catenin/TCF targets Cyclin D1 and c-Myc in PC3 cells. Expression of tetracycline-inducible ALT-PTK6 blocked the proliferation and colony formation of PC3 cells. Our findings suggest that ALT-PTK6 is able to negatively regulate growth and modulate PTK6 activity, protein-protein associations and/or subcellular localization. Fully understanding functions of ALT-PTK6 and its impact on PTK6 signaling will be critical for development of therapeutic strategies that target PTK6 in cancer.

Project description:Although fine-needle aspiration (FNA) biopsy of thyroid nodules is very sensitive in detecting thyroid malignancy, it remains ambiguous in 20-30% of cases. Current biomarkers for thyroid cancer lack either the sensitivity or specificity to substantially address this clinical problem. The aim of this study was to investigate the gene expression patterns of human telomerase reverse transcriptase (hTERT) alternative splice variants in benign and malignant thyroid tumors in an attempt to find a more reliable biomarker in the differential diagnosis of thyroid nodules.One hundred and thirty-three thyroid tumors from eight histopathological tumor types were collected from patients undergoing thyroid surgery at Johns Hopkins Hospital. Gene expression patterns of hTERT alternative splice variants were investigated in the tumors by nested reverse transcriptase-PCR. Telomerase enzyme activity was evaluated in a subset of 16 samples associated with the different hTERT patterns. Association of c-myc expression and hTERT patterns was also examined.Malignant thyroid tumors exhibited a greater proportion of the active full-length hTERT transcript (0.57 +/- 0.15) than inactive splice variants, alpha(-) (0.13 +/- 0.02), or beta(-)/alpha(-)beta(-) deletion transcripts (0.30 +/- 0.11; p < 0.001). The opposite was observed in benign tumors, which exhibited greater proportions of beta(-)/alpha(-)beta(-) deletion transcripts (0.64 +/- 0.08) than either the full-length (0.19 +/- 0.06) or alpha(-) deletion transcripts (0.17 +/- 0.02; p < 0.001). Similar results were observed among a diagnostically challenging subset of 50 thyroid tumors that were suspicious for malignancy on FNA. Further, increased telomerase enzymatic activity was only associated with expression of the full-length hTERT isoform. In contrast, c-myc expression, which has been implicated in hTERT regulation, correlated with overall hTERT transcription without specificity for expression of the full-length isoform.These differences in gene expression patterns of hTERT alternative splice variants may provide a useful adjunct to FNA diagnosis of suspicious thyroid tumors.

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SZIP, an alternative splice variant of ZIP, antagonizes transcription repression and growth inhibition by ZIP.

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sZIP, an alternative splice variant of ZIP, antagonizes transcription repression and growth inhibition by ZIP.

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