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Saleem A.N.,Academia Sinica, Taiwan | Saleem A.N.,University of Mosul | Chen Y.-H.,Academia Sinica, Taiwan | Chen Y.-H.,Taiwan Mouse Clinic National Phenotyping Center | And 18 more authors.
PLoS Genetics

Protein palmitoylation has emerged as an important mechanism for regulating protein trafficking, stability, and protein- protein interactions; however, its relevance to disease processes is not clear. Using a genome-wide, phenotype driven N- ethyl-N-nitrosourea-mediated mutagenesis screen, we identified mice with failure to thrive, shortened life span, skin and hair abnormalities including alopecia, severe osteoporosis, and systemic amyloidosis (both AA and AL amyloids depositions). Whole-genome homozygosity mapping with 295 SNP markers and fine mapping with an additional 50 SNPs localized the disease gene to chromosome 7 between 53.9 and 56.3 Mb. A nonsense mutation (c.1273A>T) was located in exon 12 of the Zdhhc13 gene (Zinc finger, DHHC domain containing 13), a gene coding for palmitoyl transferase. The mutation predicted a truncated protein (R425X), and real-time PCR showed markedly reduced Zdhhc13 mRNA. A second gene trap allele of Zdhhc13 has the same phenotypes, suggesting that this is a loss of function allele. This is the first report that palmitoyl transferase deficiency causes a severe phenotype, and it establishes a direct link between protein palmitoylation and regulation of diverse physiologic functions where its absence can result in profound disease pathology. This mouse model can be used to investigate mechanisms where improper palmitoylation leads to disease processes and to understand molecular mechanisms underlying human alopecia, osteoporosis, and amyloidosis and many other neurodegenerative diseases caused by protein misfolding and amyloidosis. © 2010 Saleem et al. Source

Yu Y.-R.,National Yang Ming University | You L.-R.,National Yang Ming University | Yan Y.-T.,National Yang Ming University | Yan Y.-T.,Academia Sinica, Taiwan | And 2 more authors.
Human Molecular Genetics

OVCA1/DPH1 (OVCA1) encodes a component of the diphthamide biosynthesis pathway and is located on chromosome 17p13.3. Deletions in this region are associated with Miller-Dieker syndrome (MDS). Ovca1/ Dph1 (Ovca1)-null mice exhibit multiple developmental defects, including cleft palate, growth restriction and perinatal lethality, suggesting a role in the craniofacial abnormalities associated with MDS. Conditional ablation of Ovca1 in neural crest cells, but not in cranial paraxial mesoderm, also results in cleft palate and shortened lower jawphenotypes, similar toOvca1-null embryos.Expression of transgenicmyc-taggedOvca1 in craniofacial structures can partially rescue the cleft palate and shortened mandible of Ovca1-null embryos. Interestingly, Ovca1-null mutants are resistant to conditional expression of diphtheria toxin subunit A in both neural crest cell and paraxial mesoderm derivatives. However, OVCA1-dependent diphthamide biosynthesis is essential for neuralcrestcell-derivedcraniofacialdevelopmentbut that isdispensableforparaxialmesodermal-derivedcraniofacial structures inmammals. These findings suggest thatOVCA1 deficiency in the neural crest contributes to the craniofacial abnormalities in patients with MDS. Also, our findings provide new insights into the molecular and cellular mechanisms that lead to the craniofacial defects of MDS. © The Author 2014.Published by Oxford University Press. All rights reserved. Source

Liang C.-C.,National Yang Ming University | Lu T.-L.,National Yang Ming University | Yu Y.-R.,National Yang Ming University | You L.-R.,National Yang Ming University | And 2 more authors.

Thymoma is the most commonly identified cancer in the anterior mediastinum. To date, the causal mechanism that drives thymoma progression is not clear. Here, we generated K5-ΔN64Ctnnb1/ERT2 transgenic mice, which express an N-terminal deletion mutant of β-catenin fused to a mutated ligand-binding domain of estrogen receptor (ERT2) under the control of the bovine cytokeratin 5 (K5) promoter. The transgenic mouse lines named Tg1 and Tg4 were characterized. Forced expression of ΔN64Ctnnb1/ERT2 in the Tg1 and Tg4 mice developed small thymoma lesions in response to tamoxifen treatment. In the absence of tamoxifen, the Tg1 mice exhibited leaky activation of β-catenin, which activated the TOP-Gal transgene and Wnt/β-catenin-targeted genes. As the Tg1 mice aged in the absence of tamoxifen, manifest thymomas were found at 10-12 months. Interestingly, we detected loss of AIRE and increase of p63 in the thymomas of Tg1 mice, similar to that observed in human thymomas. Moreover, the β5t protease subunit, which was reported as a differential marker for human type B3 thymoma, was expressed in the Tg1 thymomas. Thus, the Tg1 mice generated in this study accurately mimic the characteristics of human thymomas and may serve as a model for understanding thymoma pathogenesis. Source

Lu T.-L.,National Yang Ming University | Huang Y.-F.,National Yang Ming University | You L.-R.,National Yang Ming University | Chao N.-C.,National Yang Ming University | And 5 more authors.
American Journal of Pathology

Prostate glands comprise two major epithelial cell types: luminal and basal. Luminal cells have long been considered the cellular origin of prostate cancer (CaP). However, recent evidence from a prostate regeneration assay suggests that prostate basal cells can also give rise to CaP. Here, we characterize Pten-deficient prostate lesions arising from keratin 5-expressing basal cells in a temporally controlled system in mice. Pten-deficient prostate lesions arising from basal cells exhibited luminal phenotypes with higher invasiveness, and the cell fate of Pten-deficient basal cells was traced to neoplastic luminal cells. After temporally ablating Pten in keratin 8-expressing luminal cells, luminal-derived Pten-deficient prostate tumors exhibited slower disease progression, compared with basal-derived tumors, within 13 weeks after Pten ablation. Cellular proliferation was significantly increased in basal-derived versus luminal-derived Pten-deficient prostate lesions. Increased tumor invasion into the smooth muscle layer and aberrantly regulated aggressive signatures (Smad4 and Spp1) were identified exclusively in basal-derived Pten-deficient lesions. Interestingly, p63-expressing cells, which represent basal stem and progenitor cells of basal-derived Pten-deficient prostate lesions, were significantly increased, relative to cells of the luminal-derived prostate lesion. Furthermore, castration did not suppress cellular proliferation of either basal-derived or luminal-derived Pten-deficient prostate tumors. Taken together, our data suggest that, although prostate malignancy can originate from both basal and luminal populations, these two populations differ in aggressive potential. Copyright © 2013 American Society for Investigative Pathology. Source

Weng S.-Y.,National Taiwan University | Weng S.-Y.,Academia Sinica, Taiwan | Yang C.-Y.,Academia Sinica, Taiwan | Li C.-C.,National Yang Ming University | And 11 more authors.
Journal of Hepatology

Background & Aims: Mcl-1-deficient hepatocytes are prone to undergo apoptosis. The tumor suppressor protein p53 plays an important role in apoptosis control as well as other cellular responses. This study was initially aimed to examine whether p53 was involved in Mcl-1 deficiency-induced apoptosis of hepatocytes. Methods: Hepatocyte-specific Mcl-1 knockout (Alb-Mcl-1 -/-) mice and Alb-Mcl-1-/- mice in wild-type or p53-deficient background were generated and characterized. Results: Alb-Mcl-1-/- mice were viable, but their liver cells were prone to undergo apoptosis and manifested a slightly elevated level of p53. To examine the role of p53 in Alb-Mcl-1-/- livers, Alb-Mcl-1-/- mice without p53 (DKO mice) were characterized. Unexpectedly, although p53-deficient mice appeared to be developmentally normal, DKO mice were highly susceptible to neonatal death (∼60%). Further analysis revealed that such an early lethality was likely due to hepatic failure caused by a marked reduction of fully-differentiated hepatocytes at the perinatal/neonatal stage. Moreover, those DKO mice that did survive to adulthood manifested more severe liver damage than Alb-Mcl-1-/- mice, suggesting that p53 was activated in Alb-Mcl-1-/- livers to promote cell survival. Microarray followed by quantitative PCR analysis suggested that p21Waf1/Cip1, one p53 target gene with apoptosis-inhibitory function, is likely involved in the protective role of p53 in Alb-Mcl-1-/- livers. Moreover, we demonstrated that loss of p53 promoted liver fibrosis and tumor development in Alb-Mcl-1 -/- mice. Conclusions: This study revealed an unexpected synergism between Mcl-1 and p53 in protecting from hepatic injury, fibrosis, and cancer. © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Source

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