FIN13, A NOVEL GROWTH FACTOR-INDUCIBLE SERINE-THREONINE PHOSPHATASE WHICH CAN INHIBIT CELL-CYCLE PROGRESSION

We have identified a novel type 2C serine-threonine phosphatase, FIN13 , whose expression is induced by fibroblast growth factor 4 and serum in late G(1) phase, The protein encoded by FIN13 cDNA includes N- and C-terminal domains with significant homologies to type 2C phosphatases , a domain homologous to collagen, and an acidic domain, FIN13 express ion predominates in proliferating tissues, Bacterially expressed FIN13 and FIN13 expressed in mammalian cells exhibit serine-threonine phosp hatase activity, which requires Mn2+ and is insensitive to inhibition by okadaic acid, FIN13 is localized in the nuclei of transiently trans fected cells, Cotransfection of FIN13-expressing plasmids with a plasm id that expresses the neomycin resistance gene inhibits the growth of drug-resistant colonies in NIH 3T3, HeLa and Rat-1 cells, In transient ly transfected cells, FIN13 inhibits DNA synthesis and results in the accumulation of cells in G(1) and early S phases, Similarly, the induc tion of expression of FIN13 under the control of a tetracycline-regula ted promoter in NIH 3T3 cells leads to growth inhibition, with accumul ation of cells in G(1) and early S phases, Thus, overexpression and/or unregulated expression of FIN13 inhibits cell cycle progression, indi cating that the physiological role of this phosphatase may be that of regulating the orderly progression of cells through the mitotic cycle by dephosphorylating specific substrates which are important for cell proliferation.