The leucine zipper putative tumor suppressor 2 protein LZTS2 regulates kidney development.
ABSTRACT Members of the leucine zipper putative tumor suppressor (LZTS) family play crucial roles in transcription modulation and cell cycle control. We previously demonstrated that LZTS2 functions as a novel β-catenin-interacting protein and represses β-catenin-mediated transcription on T-cell factor/lymphoid enhancing factor. Here, we investigate the biological role of LZTS2 using newly established Lzts2 KO mice. Homozygosity for loss-of-function of the Lzts2-targeted allele resulted in severe kidney and urinary tract developmental defects, including renal/ureteral duplication, hydroureter, and hydronephrosis, which were visible prenatally. Altered ureteric bud outgrowth was identified in Lzts2 null embryos. Further analysis indicated that β-catenin subcellular localization was altered in fibroblasts isolated from Lzts2 null embryos. In addition, Wnt growth factor-induced β-catenin-mediated transcriptional activity was increased in Lzts2 null fibroblasts, suggesting a direct role for Lzts2 in the Wnt signaling pathway. These data demonstrate a critical role of LZTS2 in renal development and implicate LZTS2 as a critical regulator of β-catenin-mediated nephrogenesis.
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ABSTRACT: Using an Lzts2-knockout (KO) mouse model, we characterize the biological role of Lzts2 in tumorigenesis. Both heterozygous and homozygous deletion of the Lzts2-targeted allele in mice shows an increased incidence in spontaneous tumor development, though Lzts2-homozygous knockout mice show much higher incidences than heterozygous mice. Treatment of Lzts2-deficient mice with a carcinogen, N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN), increases the susceptibility to BBN-induced bladder carcinoma development. Further analyses of mouse embryo fibroblasts (MEFs) isolated from Lzts2 knockout embryos show that loss of Lzts2 enhances cell growth. In addition, a pronounced induction of Wnt3a conditioned medium in cell growth appears in Lzts2 null MEFs, suggesting a regulatory role of Lzts2 in Wnt/β-catenin-mediated cell proliferation. Reduction of LZTS2 protein expression was also observed in human prostate cancer tissue samples. These data provide the first line of evidence demonstrating that deletion of Lzts2 increases the susceptibility of spontaneous and carcinogen-induced tumor development, which may be mediated by dysregulation of Wnt/β-catenin signaling.Journal of Biological Chemistry 12/2012; DOI:10.1074/jbc.M112.417568 · 4.60 Impact Factor
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ABSTRACT: ZMIZ2, also named ZIMP7, is a PIAS-like protein and a transcriptional co-activator. In this study, we investigated the interaction between ZMIZ2 and β-catenin, a key regulator of the Wnt signaling pathway. We demonstrated that the expression of exogenous ZMIZ2 augments TCF (T cell factor) and β-catenin mediated transcription. In contrast, shRNA knockdown of ZMIZ2 expression specifically represses the enhancement of TCF/β-catenin mediated transcription by ZMIZ2. Using Wnt3a conditioned media (Wnt3a-CM), we demonstrated that ZMIZ2 can enhance Wnt ligand induced TCF/β-catenin mediated transcription. We also showed a promotional role of ZMIZ2 in enhancing β-catenin downstream target gene expression in human cells and in Zmiz2 null (Zmiz2-/-) mouse embryonic fibroblasts (MEFs). The regulatory role of Zmiz2 in Wnt induced TCF/β-catenin mediated transcription can be restored in Zmiz2-/- MEFs that were infected with adenoviral expression vectors for Zmiz2. Moreover, enhancement of Zmiz2 on TCF/β-catenin mediated transcription was further demonstrated in Zmiz2 knockout and Axin2 reporter compound mice. Furthermore, the protein-protein interaction between ZMIZ2 and β-catenin was identified by co-immunoprecipitation and in vitro protein pulldown assays. We also observed recruitment of endogenous ZMIZ2 onto the promoter region of the Axin 2 gene, a β-catenin downstream target promoter, in a Wnt ligand inducible manner. Finally, a promotional role of ZMIZ2 on cell growth was demonstrated in human cell lines and Zmiz2 knockout MEFs. Our findings demonstrate a novel interaction between ZMIZ2 and β-catenin, and elucidate a novel mechanism for PIAS like proteins in regulating Wnt signaling pathways.Journal of Biological Chemistry 10/2013; 288(50). DOI:10.1074/jbc.M113.529727 · 4.60 Impact Factor