Mts1 (S100A4) is a calcium-binding protein of the EF-hand type, belonging to the S100 family of proteins. The mts1/S100A4 gene was originally isolated from tumor cell lines, and the protein is believed to play an important role in tumor progression. More recently, oligomeric, but not dimeric, forms of Mts1 have been shown to have a neuritogenic effect when added extracellularly to hippocampal neurons. Here we show increased neurite outgrowth in two other cell types, dopaminergic and cerebellar neurons, in response to treatment with Mts1 oligomers. Moreover, we demonstrate that Mts1 acts as a neuroprotectant in primary cerebellar, dopaminergic, and hippocampal neurons induced to undergo cell death. Interestingly, the survival of the cerebellar and hippocampal neurons increased as a result of treatment with Mts1 not only in oligomeric form but also--although to a lesser extent--in dimeric form. The inhibition of death in cerebellar neurons by Mts1 was accompanied by an inhibition of DNA fragmentation, but Mts1 did not affect the activity of caspases-3 and -6. In hippocampal neurons, cell death induced by the amyloid-beta peptide (Abeta(25-35)) was characterized by an increase in caspase-3 and -6 activity, but no DNA fragmentation was observed. As in cerebellar neurons, the induced increase in caspase activity in hippocampal neurons was not affected by Mts1.