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

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-eta 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-eta, and PMA inhibits their proliferation. Conversely, PMA increases proliferation of U-1242 cells that are stably transfected with PKC-eta (U-1242-PKC-eta). PMA treatment also stimulates proliferation of U-251 cells, which express PKC-eta. Here, we determined that extracellular signal-regulated kinase (ERK) and Elk-1 are downstream targets of PKC-eta. Elk-1-mediated transcriptional activity correlates with the PKC-eta-mediated mitogenic response. Pretreatment of U-1242-PKC-eta 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-eta 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-eta-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.

• Authors: R M Uht, S Amos, P M Martin, A E Riggan, I M Hussaini
• Journal: Oncogene (Oncogene) Vol. 26 Issue 20 Pg. 2885-93 (May 03 2007) ISSN: 0950-9232 [Print] England
• PMID: 17146445 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Isoenzymes
• Transcription Factor AP-1
• ets-Domain Protein Elk-1
• Epidermal Growth Factor
• protein kinase C eta
• Protein Kinase C
• Extracellular Signal-Regulated MAP Kinases
• Tetradecanoylphorbol Acetate

Topics

• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Epidermal Growth Factor (pharmacology)
• Extracellular Signal-Regulated MAP Kinases (metabolism, physiology)
• Genes, fos (physiology)
• Genes, jun (physiology)
• Glioblastoma (pathology)
• Humans
• Isoenzymes (physiology)
• Models, Biological
• Phosphorylation
• Protein Kinase C (physiology)
• Signal Transduction
• Tetradecanoylphorbol Acetate (pharmacology)
• Transcription Factor AP-1 (genetics)
• Transcription, Genetic (genetics)
• Transfection
• ets-Domain Protein Elk-1 (physiology)