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Differentiative pathway activated by 3‐aminobenzamide, an inhibitor of PARP, in human osteosarcoma MG‐63 cells
Author(s) -
De Blasio A.,
Messina C.,
Santulli A.,
Mangano V.,
Di Leonardo E.,
D’Anneo A.,
Tesoriere G.,
Vento R.
Publication year - 2005
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2004.12.028
Subject(s) - osteopontin , downregulation and upregulation , cyclin d1 , reprogramming , hyperphosphorylation , cancer research , microbiology and biotechnology , chemistry , e2f , retinoblastoma protein , alkaline phosphatase , osteocalcin , cell growth , biology , phosphorylation , gene expression , cell cycle , gene , endocrinology , biochemistry , enzyme
This study describes the molecular mechanism by which treatment with 3‐AB, a potent inhibitor of PARP, allows human osteosarcoma MG‐63 cells to restrict growth and enter differentiation. Our findings show that in MG‐63 cells, aberrant gene expression keeps Rb protein constitutively inactivated through hyperphosphorylation and this promotes uncontrolled proliferation of the cells. After 3‐AB‐treatment, the poly(ADP‐ribosyl)ation of nuclear proteins markedly decreases and this results in an increase in both the hypophosphorylated active form of Rb and pRb/E2F complexes. These effects are accompanied by G1 arrest, downregulation of gene products required for proliferation (cyclin D1, β‐catenin, c‐Jun, c‐Myc and Id2) and upregulation of those implicated in the osteoblastic differentiation (p21/Waf1, osteopontin, osteocalcin, type I collagen, N‐cadherins and alkaline phosphatase). Our study suggests that use of PARP inhibitors may induce a remodeling of chromatin with the reprogramming of gene expression and the activation of differentiation.