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 grow th 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), Expres sion of immediate-early genes of the c-fos and c-jun families, whose t ranscription and activation are regulated by MAP kinases, is different ially induced by insulin and TPA, Whereas insulin stimulates prolonged induction of c-jun, but not of junB mRNA, resulting in c-jun expressi on during the entire G(1) period, the growth inhibitor TPA induces jun B much longer than c-jun. Inhibition of the Erk2 pathway by PD98059, s pecific for the upstream MAP kinase kinase (MEK1), abolishes TPA-stimu lated junB but not insulin-induced c-jun, In agreement with this, insu lin readily stimulates Jun kinase (JNK), whereas TPA does not, Further more, insulin-induced pRB hyperphosphorylation at the G(1)-S transitio n and S-phase entry is insensitive to MAP kinase inhibition by PD98059 , On the other hand, PD98059 reverts the inhibitory effect of TPA on c ell cycle entry as web as on pRB hyperphosphorylation, indicating that Erk effecters function as inhibitors of proliferation in MCF7 cells.