NF-kappa B/RelA transactivation is required for atypical protein kinase C iota-mediated cell survival

In chronic myelogenous leukemia (CML), the oncogene bcr-abl encodes a dysre gulated tyrosine kinase that inhibits apoptosis. We showed previously that human erythroleukemia K562 cells are resistant to antineoplastic drug (taxo l)-induced apoptosis through the atypical protein kinase C iota isozyme (PK C iota), a kinase downstream of Bcr-Abl. The mechanism(s) by which PKC iota mediates cell survival to taxol is unknown. Here we demonstrate that PKC i ota requires the transcription factor nuclear factor-kappaB (NF-kappaB) to confer cell survival. At apoptosis-inducing concentrations, taxol weakly in duces I kappaB alpha proteolysis and NF-kappaB translocation in K562 cells, but potently induces its transcriptional activity. Inhibition of NF-kappaB activity (by blocking l kappaB alpha degradation) significantly sensitizes cells to taxol-induced apoptosis. Likewise, K562 cells expressing antisens e PKC iota mRNA or kinase dead PKC iota (PKC iota -KD) are sensitized to ta xol; these cells are rescued from apoptosis by NF-kappaB overexpression. Ex pression of constitutively active PKC iota (PKC iota -CA) upregulates NF-ka ppaB transactivation and rescues cells from apoptosis in the absence of Bcr -Abl tyrosine kinase activity. Using a chimeric GAL4-RelA transactivator, w e find that taxol potently activates GAL4-RelA-dependent transcription. Thi s activation was further upregulated by expression of PKC iota -CA and inhi bited by expression of PKC iota -KD. Our results indicate that RelA transac tivation is an important downstream target of the PKC iota -mediated Bcr-Ab l signaling pathway and is required for resistance to taxol-induced apoptos is.