Protein kinase C-zeta reverts v-raf transformation of NIH-3T3 cells.
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.
Kieser
A
A
Institut für Klinische Molekularbiologie und Tumorgenetik, Forschungszentrum für Umwelt and Gesundheit, München, Germany.
Seitz
T
T
Adler
H S
HS
Coffer
P
P
Kremmer
E
E
Crespo
P
P
Gutkind
J S
JS
Henderson
D W
DW
Mushinski
J F
JF
Kolch
W
W
Mischak
H
H
D016475:3T3 Cells; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D002455:Cell Division; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D051766:Early Growth Response Protein 1; D015972:Gene Expression Regulation, Neoplastic; D016153:Genes, Suppressor; D017874:Immediate-Early Proteins; D048728:MAP Kinase Kinase Kinase 1; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D027384:Oncogene Proteins v-raf; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000235:genetics; D019908:Proto-Oncogene Proteins c-raf; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics*; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D000099221:Protein Kinase C zeta
D017871:Calcium-Calmodulin-Dependent Protein Kinases; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; D017874:Immediate-Early Proteins; D048728:MAP Kinase Kinase Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D027384:Oncogene Proteins v-raf; D011493:Protein Kinase C; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D019908:Proto-Oncogene Proteins c-raf; D015682:Retroviridae Proteins, Oncogenic; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D000099221:Protein Kinase C zeta; C486109:Egr1 protein, mouse; C482576:MAP3K1 protein, human; C482578:Map3k1 protein, mouse