NF-κB/RelA transactivation is required for atypical protein kinase Cl-mediated cell survival

Ying Lu, Lee Jamieson, Allan R. Brasier, Alan P. Fields

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

In chronic myelogenous leukemia (CML), the oncogene bcr-abl encodes a dysregulated tyrosine kinase that inhibits apoptosis. We showed previously that human erythroleukemia K562 cells are resistant to antineoplastic drug (taxol)-induced apoptosis through the atypical protein kinase C iota isozyme (PKCl), a kinase downstream of Bcr-Abl. The mechanism(s) by which PKCl mediates cell survival to taxol is unknown. Here we demonstrate that PKCl requires the transcription factor nuclear factor-κB (NF-κB) to confer cell survival. At apoptosis-inducing concentrations, taxol weakly induces IκBα proteolysis and NF-κB translocation in K562 cells, but potently induces its transcriptional activity. Inhibition of NF-κB activity (by blocking IκBα degradation) significantly sensitizes cells to taxol-induced apoptosis. Likewise, K562 cells expressing antisense PKCl mRNA or kinase dead PKCl (PKCl-KD) are sensitized to taxol; these cells are rescued from apoptosis by NF-κB overexpression. Expression of constitutively active PKCl (PKCl-CA) upregulates NF-κB transactivation and rescues cells from apoptosis in the absence of Bcr-Abl tyrosine kinase activity. Using a chimeric GAL4-RelA transactivator, we find that taxol potently activates GAL4-RelA-dependent transcription. This activation was further upregulated by expression of PKCl-CA and inhibited by expression of PKCl-KD. Our results indicate that RelA transactivation is an important downstream target of the PKCl-mediated Bcr-Abl signaling pathway and is required for resistance to taxol-induced apoptosis.

Original languageEnglish (US)
Pages (from-to)4777-4792
Number of pages16
JournalOncogene
Volume20
Issue number35
DOIs
StatePublished - Aug 9 2001

Fingerprint

Paclitaxel
Protein Kinases
Transcriptional Activation
Cell Survival
Apoptosis
K562 Cells
Phosphotransferases
bcr-abl Fusion Proteins
abl Genes
Leukemia, Erythroblastic, Acute
Trans-Activators
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Antineoplastic Agents
Protein-Tyrosine Kinases
Isoenzymes
Proteolysis
Transcription Factors
Up-Regulation
Messenger RNA

Keywords

  • Apoptosis
  • Nuclear factor-κB
  • Protein kinase C iota
  • Taxol

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

NF-κB/RelA transactivation is required for atypical protein kinase Cl-mediated cell survival. / Lu, Ying; Jamieson, Lee; Brasier, Allan R.; Fields, Alan P.

In: Oncogene, Vol. 20, No. 35, 09.08.2001, p. 4777-4792.

Research output: Contribution to journalArticle

Lu, Ying ; Jamieson, Lee ; Brasier, Allan R. ; Fields, Alan P. / NF-κB/RelA transactivation is required for atypical protein kinase Cl-mediated cell survival. In: Oncogene. 2001 ; Vol. 20, No. 35. pp. 4777-4792.
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