protein and induction of p21/WAF1 in confluent cells, thus providing a link between nSMase2 and key regulators of cell cycle. Further, PP1, a lipid-regulated protein phosphatase, was implicated as acting downstream of nSMase2 in regulating cell motility during cell confluence (Marchesini et al., 2007). On the other hand, the antioxidants CoQ inhibited serum deprivation-induced activation of nSMase and ceramide accumulation (Navas et al., 2002). Surprisingly, while nSMase2 was reported to be distributed throughout MCF-7 cells under subconfluent condition, the protein became predominantly located at the PM in confluent, growth-arrested cells. This further supports the hypothesis that the PM is the major site of nSMase2 action. Finally, a more recent study demonstrated induction of nSMase2 mRNA and ceramide levels by retinoic acid (Somenzi et al., 2007). As retinoic acid is also known to induce G0/G1 arrest, this provides further evidence that nSMase2 is an important regulator of cell growth and the cell cycle.
