Role of protein kinase C-δ (PKC-δ) in the generation of the effects of IFN-α in chronic myelogenous leukemia cells

Surinder Kaur, Simrit Parmar, Jessica Smith, Efstratios Katsoulidis, Yongzhong Li, Antonella Sassano, Beata Majchrzak, Shahab Uddin, Martin S. Tallman, Eleanor N. Fish, Leonidas C. Platanias*

*Corresponding author for this work

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Objective. The mechanisms by which interferon α (IFN-α) 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-δ, is activated during treatment of BCR-ABL cells with IFN-α 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-δ in response to IFN-α in CML-derived cell lines. The effects of pharmacological inhibition of PKC-δ on the suppressive effects of IFN-α on leukemic CFU-GM progenitors from CML patients were assessed by clonogenic assays in methylcellulose. Results. IFN-α treatment of the sensitive CML-derived KT-1 cell line resulted in phosphorylation of PKC-δ and activation of its kinase domain. Such phosphorylation/activation of PKC-δ was required for phosphorylation of Stat1 on serine 727, as inhibition of PKC-δ activity blocked the IFN-α-dependent serine phosphorylation of Stat1 and IFN-α-inducible gene transcription. IFN-α 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-δ pharmacologic inhibitor rottlerin. Conclusion. Taken altogether, our data demonstrate that PKC-δ 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.

Original languageEnglish (US)
Pages (from-to)550-557
Number of pages8
JournalExperimental Hematology
Volume33
Issue number5
DOIs
StatePublished - May 2005

ASJC Scopus subject areas

  • Molecular Biology
  • Hematology
  • Genetics
  • Cell Biology
  • Cancer Research

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