Regulation of ribosomal protein S6 kinase in human mammary tumor cells: effect of estrogen, growth factors and phorbol ester.

Growth of human mammary tumor cells ZR-75-1 is stimulated by estradiol (E2), epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I). In these cells ribosomal protein S6 kinase is activated by EGF, IGF-I, insulin and phorbol 12-myristate 13-acetate (TPA) but not by E2. The human mammary tumor cell line MDA-MB 231, which is E2-receptor negative, has receptors for EGF, IGF-I and insulin but is unresponsive to these factors in terms of growth and S6 kinase activation. The role of protein kinase C (PKC) in the activation of S6 kinase by growth factors and TPA was investigated in ZR-75-1 cells. Down regulation of PKC activity by treatment with TPA for 48-h blocks the stimulation of S6 kinase by TPA but leaves the activation by EGF, IGF-I and insulin unaffected. In intact ZR-75-1 cells staurosporine blocks activation of S6 kinase by EGF and TPA, however with different IC50. The results show that S6 kinase is not activated by estradiol, that its activation by EGF, IGE-I and insulin does not depend on the presence of PKC activity and that its activation by TPA is mediated by a different (PKC-dependent) pathway.