Protein kinase C alpha but not PKCzeta suppresses intestinal tumor formation in ApcMin/+ mice.
Members of the protein kinase C (PKC) family of serine/threonine kinases play key regulatory roles in numerous cellular processes, including differentiation and proliferation. Of the 11 mammalian PKC isoforms known, several have been implicated in tumor development and progression. However, in most cases, isotype specificity is poorly defined, and even contrary functions for a single PKC have been reported mostly because appropriate molecular and genetic tools were missing to specifically assess the contribution of single PKC isoforms in vivo. In this report, we therefore used PKC genetic targeting to study the role of PKCalpha and PKCzeta in colorectal cancer. Both isoforms were found to be strongly down-regulated in intestinal tumors of ApcMin/+ mice. A deletion of PKCzeta did not affect tumorigenesis in this animal model. In contrast, PKCalpha-deficient ApcMin/+ mice developed more aggressive tumors and died significantly earlier than their PKCalpha-proficient littermates. Even without an additional Apc mutation, PKCalpha knockout mice showed an elevated tendency to develop spontaneous intestinal tumors. Transcriptional profiling revealed a role for this kinase in regulating epidermal growth factor receptor (EGFR) signaling and proposed a synergistic mechanism for EGFR/activator protein and WNT/APC pathways in mediating intestinal tumor development.
Oster
Henrik
H
Laboratory for Signal Transduction, Max Planck Institute of Experimental Endocrinology and Department of Nephrology, Hannover Medical School, Hannover, Germany.
Leitges
Michael
M
D000818:Animals; D066259:Betacellulin; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015536:Down-Regulation; D004815:Epidermal Growth Factor / Q000096:biosynthesis / Q000235:genetics; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics; D020869:Gene Expression Profiling; D016758:Genes, jun; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D007417:Intestinal Polyps / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011493:Protein Kinase C / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051571:Protein Kinase C-alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014158:Transcription, Genetic; D000099221:Protein Kinase C zeta
D066259:Betacellulin; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D036341:Intercellular Signaling Peptides and Proteins; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D000099221:Protein Kinase C zeta; C587852:Btc protein, mouse