Drugs affecting prelamin A processing: Effects on heterochromatin organization. (Articolo in rivista)

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  • Drugs affecting prelamin A processing: Effects on heterochromatin organization. (Articolo in rivista) (literal)
Anno
  • 2008-01-01T00:00:00+01:00 (literal)
Alternative label
  • Mattioli E, Columbaro M, Capanni C, Santi S, Maraldi NM, D'Apice MR, Novelli G, Riccio M, Squarzoni S, Foisner R, Lattanzi G. (2008)
    Drugs affecting prelamin A processing: Effects on heterochromatin organization.
    in Experimental cell research
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Mattioli E, Columbaro M, Capanni C, Santi S, Maraldi NM, D'Apice MR, Novelli G, Riccio M, Squarzoni S, Foisner R, Lattanzi G. (literal)
Pagina inizio
  • 453 (literal)
Pagina fine
  • 462 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroVolume
  • 314 (literal)
Rivista
Note
  • ISI Web of Science (WOS) (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
  • IGM-CNR, Unit of Bologna, c/o IOR, Via di Barbiano 1/10 I-40136 Bologna, Italy; Laboratory of Cell Biology, Istituto Ortopedico Rizzoli, Bologna, Italy; Department of Anatomy and Histology, University of Modena and Reggio Emilia, Modena, Italy; Department of Biopathology and Diagnostic Imaging, University of Rome Tor Vergata, Rome, Italy; Max F. Perutz Laboratories, Medical University of Vienna, Vienna, Austria (literal)
Titolo
  • Drugs affecting prelamin A processing: Effects on heterochromatin organization. (literal)
Abstract
  • Increasing interest in drugs acting on prelamin A has derived from the finding of prelamin A involvement in severe laminopathies. Amelioration of the nuclear morphology by inhibitors of prelamin A farnesylation has been widely reported in progeroid laminopathies. We investigated the effects on chromatin organization of two drugs inhibiting prelamin A processing by an ultrastructural and biochemical approach. The farnesyltransferase inhibitor FTI-277 and the non-peptidomimetic drug N-acetyl-S-farnesyl-l-cysteine methylester (AFCMe) were administered to cultured control human fibroblasts for 6 or 18 h. FTI-277 interferes with protein farnesylation causing accumulation of non-farnesylated prelamin A, while AFCMe impairs the last cleavage of the lamin A precursor and is expected to accumulate farnesylated prelamin A. FTI-277 caused redistribution of heterochromatin domains at the nuclear interior, while AFCMe caused loss of heterochromatin domains, increase of nuclear size and nuclear lamina thickening. At the biochemical level, heterochromatin-associated proteins and LAP2alpha were clustered at the nuclear interior following FTI-277 treatment, while they were unevenly distributed or absent in AFCMe-treated nuclei. The reported effects show that chromatin is an immediate target of FTI-277 and AFCMe and that dramatic remodeling of chromatin domains occurs following treatment with the drugs. These effects appear to depend, at least in part, on the accumulation of prelamin A forms, since impairment of prelamin A accumulation, here obtained by 5-azadeoxycytidine treatment, abolishes the chromatin effects. These results may be used to evaluate downstream effects of FTIs or other prelamin A inhibitors potentially useful for the therapy of laminopathies. (literal)
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