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  • Title: Cytotoxicity induced by manipulation of signal transduction pathways is associated with down-regulation of Bcl-2 but not Mcl-1 in MCF-7 human breast cancer.
    Author: Hu Y, Dragowska WH, Wallis A, Duronio V, Mayer L.
    Journal: Breast Cancer Res Treat; 2001 Nov; 70(1):11-20. PubMed ID: 11767000.
    Abstract:
    We examined the role of Mcl-1 and Bcl-2 expression in the induction of apoptosis. through blocking protein tyrosine kinase (PTK), protein kinase C (PKC), phosphatidylinositol 3-kinase (P13-K) and mitogen-activated protein kinase (MAPK)/Erk kinase (MEK) signaling pathways by various kinase inhibitors in MCF-7 breast cancer cells. The PTK inhibitor genistein (GEN) and PKC inhibitor staurosporine (STP) down-regulated Mcl-1 and Bcl-2 expression, and induced growth inhibition by blocking at the G2/M phase of cell cycle, followed by apoptosis, leading to chromatin condensation and DNA fragmentation. LY294002 (LY)-mediated inhibition of P13-K activity down-regulated Bcl-2 but not Mcl-1 expression. triggered growth arrest at the G1/G0 phase of cell cycle and also led to apoptosis marked with chromatin condensation and DNA fragmentation. The MEK inhibitor U0126 (U0) decreased Bcl-2 expression but not Mcl-1 expression, inhibited cells growth and induced G1/G0 arrest. but in this case cell death occurred without significant apoptotic features. The kinase inhibitor concentration dependence of cytotoxicity correlated well with down-regulation of Bcl-2 but not with changes in Mcl-1 levels. This suggests that Bcl-2 plays a predominant role in the regulation of cell death induced by cell signaling alterations whereas Mcl-1 does not appear to control cell survival under these conditions in MCF-7 cells. Further studies showed that the combination of GEN, STP and LY with U0 can produce synergetic cytotoxic effects on MCF-7 cells. Our results suggest that PTK, PKC, P13-K and MEK signaling pathways can regulate Bcl-2 expression and form an integrated network that plays a critical role in cell survival.
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