1. Rapamycin treatment of Mandibuloacral dysplasia cells rescues localization of chromatin-associated proteins and cell cycle dynamics.
- Author
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Cenni V, Capanni C, Mattioli E, Columbaro M, Wehnert M, Ortolani M, Fini M, Novelli G, Bertacchini J, Maraldi NM, Marmiroli S, D'Apice MR, Prencipe S, Squarzoni S, and Lattanzi G
- Subjects
- Acro-Osteolysis metabolism, Adult, Antibiotics, Antineoplastic pharmacology, Cell Cycle drug effects, Cells, Cultured, Chromatin drug effects, Contracture metabolism, DNA Repair drug effects, DNA-Binding Proteins metabolism, Fibroblasts drug effects, Fibroblasts metabolism, Humans, Infant, Newborn, Lamin Type A, Lipodystrophy metabolism, Mandible metabolism, Membrane Proteins metabolism, Nuclear Proteins genetics, Protein Precursors genetics, Sirolimus pharmacology, Skin Abnormalities metabolism, Acro-Osteolysis drug therapy, Antibiotics, Antineoplastic therapeutic use, Lipodystrophy drug therapy, Mandible abnormalities, Nuclear Proteins metabolism, Octamer Transcription Factor-1 metabolism, Protein Precursors metabolism, Sirolimus therapeutic use
- Abstract
Lamin A is a key component of the nuclear lamina produced through post-translational processing of its precursor known as prelamin A.LMNA mutations leading to farnesylated prelamin A accumulation are known to cause lipodystrophy, progeroid and developmental diseases, including Mandibuloacral dysplasia, a mild progeroid syndrome with partial lipodystrophy and altered bone turnover. Thus, degradation of prelamin A is expected to improve the disease phenotype. Here, we show different susceptibilities of prelamin A forms to proteolysis and further demonstrate that treatment with rapamycin efficiently and selectively triggers lysosomal degradation of farnesylated prelamin A, the most toxic processing intermediate. Importantly, rapamycin treatment of Mandibuloacral dysplasia cells, which feature very low levels of the NAD-dependent sirtuin SIRT-1 in the nuclear matrix, restores SIRT-1 localization and distribution of chromatin markers, elicits release of the transcription factor Oct-1 and determines shortening of the prolonged S-phase. These findings indicate the drug as a possible treatment for Mandibuloacral dysplasia.
- Published
- 2014
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