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- Choi, WJ, et al.
(författare)
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Expression of the Hutchinson-Gilford Progeria Mutation Leads to Aberrant Dentin Formation
- 2018
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 15368-
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Tidskriftsartikel (refereegranskat)abstract
- Hutchinson-Gilford progeria syndrome (HGPS) is a rare accelerated senescence disease, manifesting dental abnormalities and several symptoms suggestive of premature aging. Although irregular secondary dentin formation in HGPS patients has been reported, pathological mechanisms underlying aberrant dentin formation remain undefined. In this study, we analyzed the mandibular molars of a tissue-specific mouse model that overexpresses the most common HGPS mutation (LMNA, c.1824C > T, p.G608G) in odontoblasts. In the molars of HGPS mutant mice at postnatal week 13, targeted expression of the HGPS mutation in odontoblasts results in excessive dentin formation and pulp obliteration. Circumpulpal dentin of HGPS mutants was clearly distinguished from secondary dentin of wild-type (WT) littermates and its mantle dentin by considering the irregular porous structure and loss of dentinal tubules. However, the dentin was significantly thinner in the molars of HGPS mutants at postnatal weeks 3 and 5 than in those of WT mice. In vitro analyses using MDPC-23, a mouse odontoblastic cell line, showed cellular senescence, defects of signaling pathways and consequential downregulation of matrix protein expression in progerin-expressing odontoblasts. These results indicate that expression of the HGPS mutation in odontoblasts disturbs physiological secondary dentin formation. In addition, progerin-expressing odontoblasts secrete paracrine factors that can stimulate odontogenic differentiation of dental pulp cells. Taken together, our results suggest that the aberrant circumpulpal dentin of HGPS mutants results from defects in physiological secondary dentin formation and consequential pathologic response stimulated by paracrine factors from neighboring progerin-expressing odontoblasts.
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- Palomar-Siles, M, et al.
(författare)
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Translational readthrough of nonsense mutant TP53 by mRNA incorporation of 5-Fluorouridine
- 2022
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Ingår i: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 13:11, s. 997-
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Tidskriftsartikel (refereegranskat)abstract
- TP53 nonsense mutations in cancer produce truncated inactive p53 protein. We show that 5-FU metabolite 5-Fluorouridine (FUr) induces full-length p53 in human tumor cells carrying R213X nonsense mutant TP53. Ribosome profiling visualized translational readthrough at the R213X premature stop codon and demonstrated that FUr-induced readthrough is less permissive for canonical stop codon readthrough compared to aminoglycoside G418. FUr is incorporated into mRNA and can potentially base-pair with guanine, allowing insertion of Arg tRNA at the TP53 R213X UGA premature stop codon and translation of full-length wild-type p53. We confirmed that full-length p53 rescued by FUr triggers tumor cell death by apoptosis. FUr also restored full-length p53 in TP53 R213X mutant human tumor xenografts in vivo. Thus, we demonstrate a novel strategy for therapeutic rescue of nonsense mutant TP53 and suggest that FUr should be explored for treatment of patients with TP53 nonsense mutant tumors.
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