The three different c-Jun N-terminal kinases (JNKs) are activated in multiple cell typesby both apoptotic and mitogenic signals, and in turn regulate the activity of transcriptionfactors such as c-Jun. Being highly homologous and ubiquitously expressed, the JNK1and JNK2 proteins have been thought to perform redundant functions in manyphysiological process. However, our data from Jnk1-/- or Jnk2-/- cells and mice suggestthat both JNK isozymes perform distinct functions in regulating cellular proliferation viadifferential regulation of c-Jun, which is a critical regulator of cell-cycle progression.Absence of JNK1, the positive regulator of c-Jun, leads to decreased fibroblastproliferation. In contrast, JNK2 deficiency leads to reduced c-Jun degradation, therebyaugmenting c-Jun levels and cellular proliferation. Various cell types includingfibroblasts, erythroblasts and hepatocytes from Jnk2-/- mice exhibit increased proliferationrates compared to their wild-type counterparts. These data therefore suggests that JNK2,in contrast to JNK1, is a negative regulator of cellular proliferation in multiple cell types.