Role of protein kinase C-delta (PKC-delta) in the generation of the effects of IFN-alpha in chronic myelogenous leukemia cells.
Posted by rob on April 29, 2005 under Uncategorized | 
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Kaur S, Parmar S, Smith J, Katsoulidis E, Li Y, Sassano A, Majchrzak B, Uddin S, Tallman MS, Fish EN, Platanias LC
Exp Hematol. 2005 May ; 33(5): 550-7
OBJECTIVE: The mechanisms by which interferon alpha (IFN-alpha) induces antileukemic responses in chronic myelogenous leukemia (CML) cells are not known. We examined whether a member of the protein kinase C (PKC) family of proteins, PKC-delta, is activated during treatment of BCR-ABL cells with IFN-alpha and participates in the induction of interferon responses. METHODS: Immunoblots and immune complex kinase assays were performed to study the phosphorylation and activation of PKC-delta in response to IFN-alpha in CML-derived cell lines. The effects of pharmacological inhibition of PKC-delta on the suppressive effects of IFN-alpha on leukemic CFU-GM progenitors from CML patients were assessed by clonogenic assays in methylcellulose. RESULTS: IFN-alpha treatment of the sensitive CML-derived KT-1 cell line resulted in phosphorylation of PKC-delta and activation of its kinase domain. Such phosphorylation/activation of PKC-delta was required for phosphorylation of Stat1 on serine 727, as inhibition of PKC-delta activity blocked the IFN-alpha-dependent serine phosphorylation of Stat1 and IFN-alpha-inducible gene transcription. IFN-alpha treatment strongly inhibited leukemic CFU-GM progenitor colony fromation from bone marrow or peripheral blood of patients with CML, and such inhibition was reversed by concomitant treatment of the cells with the PKC-delta pharmacologic inhibitor rottlerin. CONCLUSION: Taken altogether, our data demonstrate that PKC-delta plays a critical role in Type I IFN signaling in BCR-ABL expressing cells, acting as a serine kinase for Stat1, to regulate transcriptional activation of interferon-regulated genes and induction of antileukemic responses.
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