The role of MAP kinase in TPA-mediated cell cycle arrest of human breast cancer cells

In MCF7 breast cancer cells, mitogen-activated protein (MAP) kinase (i.e. Erk-1/2) is activated by the mitogen insulin, but also by the growth inhibiting agent TPA, though with very different kinetics, Insulin induces a relatively transient activation of Erk2 ( < 15 min), whereas TPA is able to induce a prolonged activation of Erk2 ( > 6 h), Expression of immediate-early genes of the c-fos and c-jun families, whose transcription and activation are regulated by MAP kinases, is differentially induced by insulin and TPA, Whereas insulin stimulates prolonged induction of c-jun, but not of junB mRNA, resulting in c-jun expression during the entire G(1) period, the growth inhibitor TPA induces junB much longer than c-jun. Inhibition of the Erk2 pathway by PD98059, specific for the upstream MAP kinase kinase (MEK1), abolishes TPA-stimulated junB but not insulin-induced c-jun, In agreement with this, insulin readily stimulates Jun kinase (JNK), whereas TPA does not, Furthermore, insulin-induced pRB hyperphosphorylation at the G(1)-S transition and S-phase entry is insensitive to MAP kinase inhibition by PD98059, On the other hand, PD98059 reverts the inhibitory effect of TPA on cell cycle entry as web as on pRB hyperphosphorylation, indicating that Erk effecters function as inhibitors of proliferation in MCF7 cells.