RESUMO
Overactivation of poly (ADP-ribose) polymerase-1 (PARP-1) triggers a noncanonical form of programmed cell death (PCD) called parthanatos, yet the mechanisms of its induction are not fully understood. We have recently demonstrated that the aggresome-like induced structures (ALIS) composed of the autophagy receptor SQSTM1/p62 and K48-linked polyubiquitinated proteins (p62-based ALIS) mediate parthanatos. In this study, we identified the D1 dopamine receptor agonist YM435 as a unique parthanatos inhibitor that acts as the disaggregating agent for the p62-based ALIS. We found that YM435 structurally reduces aggregability of the ALIS, and then increases its hydrophilicity and liquidity, which prevents parthanatos. Moreover, dopamine and L-DOPA, a dopamine precursor, also prevented parthanatos by reducing the aggregability of the ALIS. Together, these observations suggest that aggregability of the p62-based ALIS determines the sensitivity to parthanatos, and the pharmacological properties of YM435 that reduces the aggregability may be suitable for therapeutic drugs for parthanatos-related diseases such as neurodegenerative diseases.
RESUMO
Neurofibromas of neurofibromatosis 1 (NF1) are highly vascular. Because the number of PDGF beta receptors in neurofibroma-derived cultured cells (NF-derived cells) has been reported to be increased, we tested whether platelet-derived growth factor BB (PDGF-BB) could induce expression of vascular endothelial growth factor (VEGF) in NF-derived cells. When analysed by reverse transcription-polymerase chain reaction, VEGF mRNA expression was found to be stimulated by PDGF-BB and TGF-beta1. Those growth factors stimulated the secretion of VEGF from NF-derived cells. PDGF-BB furthermore induced the mitogen-activated protein kinase phosphorylation in NF-derived cells from patients with NF1. In conclusion, PDGF-BB stimulated VEGF secretion in NF-derived cells, and this stimulation is probably important in neurofibroma hypervascularization.