The protein kinase C-η isoform induces proliferation in glioblastoma cell lines through an ERK/Elk-1 pathway

Rosalie Maire Uht, S. Amos, P. M. Martin, A. E. Riggan, I. M. Hussaini

Research output: Contribution to journalArticle

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Abstract

Glioblastoma multiforme (GBM) is the highest grade of astrocytoma. GBM pathogenesis has been linked to receptor tyrosine kinases and kinases further down signal-transduction pathways - in particular, members of the protein kinase C (PKC) family. The expression and activity of various PKC isoforms are increased in malignant astrocytomas, but not in non-neoplastic astrocytes. This suggests that PKC activity contributes to tumor progression. The level of PKC-η expressed correlates with the degree of phorbol-12-myristate-13- acetate (PMA)-induced proliferation of two glioblastoma cell lines, U-1242 MG and U-251 MG. Normally, U-1242 cells do not express PKC-η, and PMA inhibits their proliferation. Conversely, PMA increases proliferation of U-1242 cells that are stably transfected with PKC-η (U-1242-PKC-η). PMA treatment also stimulates proliferation of U-251 cells, which express PKC-η. Here, we determined that extracellular signal-regulated kinase (ERK) and Elk-1 are downstream targets of PKC-η. Elk-1-mediated transcriptional activity correlates with the PKC-η-mediated mitogenic response. Pretreatment of U-1242-PKC-η cells with inhibitors of PKC or MAPK/ERK kinase (MEK) (bisindolyl maleimide (BIM) or U0126, respectively) blocked both PMA-induced Elk-1 transcriptional activity and PMA-stimulated proliferation. An overexpressed dominant-negative PKC-η reduced the mitogenic response in U-251 cells, as did reduction of Elk-1 by small interfering RNA. Taken together, these results strongly suggest that PKC-η-mediated glioblastoma proliferation involves MEK/mitogen-activated protein (MAP) kinase phosphorylation, activation of ERK and subsequently of Elk-1. Elk-1 target genes involved in GBM proliferative responses have yet to be identified.

Original languageEnglish
Pages (from-to)2885-2893
Number of pages9
JournalOncogene
Volume26
Issue number20
DOIs
StatePublished - 3 May 2007

Fingerprint

Mitogen-Activated Protein Kinase 3
Glioblastoma
Protein Kinase C
Protein Isoforms
Cell Line
Acetates
Extracellular Signal-Regulated MAP Kinases
Astrocytoma
Phosphotransferases
Mitogen-Activated Protein Kinase Kinases
Receptor Protein-Tyrosine Kinases
Mitogen-Activated Protein Kinases
Astrocytes
Small Interfering RNA
phorbol-12-myristate
Signal Transduction

Keywords

  • AP-1
  • ERK
  • Elk-1
  • Glioblastoma
  • PKC-η
  • Proliferation

Cite this

Uht, Rosalie Maire ; Amos, S. ; Martin, P. M. ; Riggan, A. E. ; Hussaini, I. M. / The protein kinase C-η isoform induces proliferation in glioblastoma cell lines through an ERK/Elk-1 pathway. In: Oncogene. 2007 ; Vol. 26, No. 20. pp. 2885-2893.
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The protein kinase C-η isoform induces proliferation in glioblastoma cell lines through an ERK/Elk-1 pathway. / Uht, Rosalie Maire; Amos, S.; Martin, P. M.; Riggan, A. E.; Hussaini, I. M.

In: Oncogene, Vol. 26, No. 20, 03.05.2007, p. 2885-2893.

Research output: Contribution to journalArticle

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T1 - The protein kinase C-η isoform induces proliferation in glioblastoma cell lines through an ERK/Elk-1 pathway

AU - Uht, Rosalie Maire

AU - Amos, S.

AU - Martin, P. M.

AU - Riggan, A. E.

AU - Hussaini, I. M.

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AB - Glioblastoma multiforme (GBM) is the highest grade of astrocytoma. GBM pathogenesis has been linked to receptor tyrosine kinases and kinases further down signal-transduction pathways - in particular, members of the protein kinase C (PKC) family. The expression and activity of various PKC isoforms are increased in malignant astrocytomas, but not in non-neoplastic astrocytes. This suggests that PKC activity contributes to tumor progression. The level of PKC-η expressed correlates with the degree of phorbol-12-myristate-13- acetate (PMA)-induced proliferation of two glioblastoma cell lines, U-1242 MG and U-251 MG. Normally, U-1242 cells do not express PKC-η, and PMA inhibits their proliferation. Conversely, PMA increases proliferation of U-1242 cells that are stably transfected with PKC-η (U-1242-PKC-η). PMA treatment also stimulates proliferation of U-251 cells, which express PKC-η. Here, we determined that extracellular signal-regulated kinase (ERK) and Elk-1 are downstream targets of PKC-η. Elk-1-mediated transcriptional activity correlates with the PKC-η-mediated mitogenic response. Pretreatment of U-1242-PKC-η cells with inhibitors of PKC or MAPK/ERK kinase (MEK) (bisindolyl maleimide (BIM) or U0126, respectively) blocked both PMA-induced Elk-1 transcriptional activity and PMA-stimulated proliferation. An overexpressed dominant-negative PKC-η reduced the mitogenic response in U-251 cells, as did reduction of Elk-1 by small interfering RNA. Taken together, these results strongly suggest that PKC-η-mediated glioblastoma proliferation involves MEK/mitogen-activated protein (MAP) kinase phosphorylation, activation of ERK and subsequently of Elk-1. Elk-1 target genes involved in GBM proliferative responses have yet to be identified.

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