Abstract
We have identified protein kinase C-zeta (PKC-zeta) as a novel suppressor of neoplastic transformation caused by the v-raf oncogene. PKC-zeta overexpression drastically retards proliferation, abolishes anchorage-independent growth, and reverts the morphological transformation of v-raf-transformed NIH-3T3 cells. The molecular basis for this effect appears to be a specific induction of junB and egr-1 expression, triggered synergistically by PKC-zeta via a Raf/Mek/MAPK-independent mechanism and v-raf. junB-promoter/CAT assays revealed that PKC-zeta directly targets the junB promoter. The induction of junB and egr-1 is linked to the v-raf transformation-suppressing effect of PKC-zeta as constitutive expression of junB and egr-1 but not of c-jun also abolishes anchorage-independent growth of v-raf-transformed NIH-3T3 cells. Moreover, junB overexpression leads to a retardation of proliferation in these cells. PKC-zeta interferes with the serum inducibility of an AP-1 reporter plasmid in v-raf-transformed NIH-3T3 cells, indicating that PKC-zeta antagonizes transformation and proliferation by down-modulating AP-1 function via induction of junB. In summary, our data suggest that PKC-zeta counteracts v-raf transformation by modulating the expression of the transcription factors junB and egr-1.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3T3 Cells
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Animals
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Calcium-Calmodulin-Dependent Protein Kinases / biosynthesis
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Calcium-Calmodulin-Dependent Protein Kinases / genetics
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Cell Division
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Cell Transformation, Neoplastic / genetics*
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / genetics
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Early Growth Response Protein 1
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Gene Expression Regulation, Neoplastic*
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Genes, Suppressor
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Immediate-Early Proteins*
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MAP Kinase Kinase Kinase 1*
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Mice
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases*
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Oncogene Proteins v-raf
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Promoter Regions, Genetic
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Protein Kinase C / biosynthesis
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Protein Kinase C / genetics
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Protein Kinase C / physiology*
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Protein Serine-Threonine Kinases / biosynthesis
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins c-jun / biosynthesis
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Proto-Oncogene Proteins c-jun / genetics
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Proto-Oncogene Proteins c-raf
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Retroviridae Proteins, Oncogenic / genetics*
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Signal Transduction
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Transcription Factor AP-1 / genetics
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Transcription Factors / biosynthesis
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Transcription Factors / genetics
Substances
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DNA-Binding Proteins
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Early Growth Response Protein 1
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Egr1 protein, mouse
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Immediate-Early Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-jun
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Retroviridae Proteins, Oncogenic
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Transcription Factor AP-1
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Transcription Factors
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Oncogene Proteins v-raf
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-raf
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protein kinase C zeta
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Protein Kinase C
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Calcium-Calmodulin-Dependent Protein Kinases
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinase 1
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MAP3K1 protein, human
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Map3k1 protein, mouse