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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[Show abstract][Hide abstract]ABSTRACT: Using an Lzts2 knock-out mouse model, we characterized 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, although Lzts2 homozygous knock-out
mice show significantly higher incidences than heterozygous mice. Treatment of Lzts2-deficient mice with a carcinogen, N-butyl-N-(4-hydroxybutyl) nitrosamine, increases the susceptibility to N-butyl-N-(4-hydroxybutyl) nitrosamine-induced bladder carcinoma development. Examination of human prostate cancer tissue specimens
shows a reduction of LZTS2 protein expression in prostate cancer cells. Further analyses of mouse embryonic fibroblasts isolated
from Lzts2 knock-out embryos show that loss of Lzts2 enhances cell growth. These data provide the first line of evidence demonstrating
that deletion of Lzts2 increases susceptibility to spontaneous and carcinogen-induced tumor development.
Preview · Article · Dec 2012 · Journal of Biological Chemistry
[Show abstract][Hide abstract]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.
Preview · Article · Oct 2013 · Journal of Biological Chemistry
[Show abstract][Hide abstract]ABSTRACT: Complete or partial trisomy 10q involves a duplication of 10q, or the long arm of chromosome 10. Distal 10q trisomy is a well-recognized and defined but rare genetic syndrome in which duplication of distal segments of 10q results in a pattern of malformations. Although abnormal chromosome phenotypes are commonly detected by visualization of chromosomes by traditional cytogenetic techniques, this approach is marginal in both diagnostic sensitivity and potential for biological interpretation, thus making implementation of advanced techniques and analysis methods an important consideration in a health service.
The present study describes the case of a Taiwanese boy from healthy parents with mental, growth, and psychomotor retardations. Additional clinical features included facial dysmorphism, microcephaly, brain atrophy, camptodactyly, and-as the first reported case-bilateral renal atrophy with chronic kidney disease stage 2 and the presence of a renal cyst in one kidney. A novel 21.8 Mb copy number variation region in chromosome region 10q23.1-10q25.1 was verified by array-comparative genomic hybridization in combination with quantitative real-time polymerase chain reaction. Subsequently, 200 protein-coding genes were identified in this copy number variation region and analyzed for their biological meaning using the database for annotation, visualization and integrated discovery.
According to the result of gene functional enrichment analysis using database for annotation, visualization and integrated discovery, the Wnt signaling pathway is the most pertinent to the gene content in the copy number variation region. A change in the expression levels of some Wnt signaling pathway components and of NFKB2 and PTEN genes due to a gain in their gene copy number may be associated with the patient's clinical outcomes including brain atrophy, bilateral renal atrophy with chronic kidney disease stage 2, a renal cyst in one kidney, and growth retardation.
Full-text · Article · Jun 2015 · BMC Research Notes