Farnesyl protein transferase inhibition interferes with activation of MAP kinase family members in human peripheral blood monocytes.
BACKGROUND
Farnesyl protein transferase inhibitors have emerged as promising novel agents for combating cancerous disease. Nevertheless, the importance for farnesyl protein transferase enzymatic activity for cellular physiology of untransformed cells remains poorly investigated.


METHODS
Peripheral blood monocytes, isolated from the blood of eight healthy volunteers, were treated with a farnesyl protein transferase inhibitor (FTI 744,832) or vehicle control for 16 hr. Subsequently cells were challenged with different concentrations of lipopolysaccharide (LPS), colony stimulating factor-1 (CSF-1), or phorbol esters for 10 min, after which the activation state of p42/p44 MAP kinase, p38 MAP kinase, and Jun-N-terminal kinase was investigated using Western blotting and phosphospecific antibodies.


RESULTS
We observed that farnesyl protein transferase inhibition abrogated activation of p38 MAP kinase by LPS, CSF-1, and phorbol esters. Also the activation of Jun-N-terminal kinase by LPS was not seen after farnesyl protein transferase inhibition. Finally, stimulation of p42/p44 MAP kinase with CSF-1 was strongly reduced by farnesyl protein transferase inhibition, whereas activation of p42/p44 MAP kinase by phorbol ester was only slightly effected.


CONCLUSIONS
Farnesyl protein transferase enzymatic activity is required for proper activation of all major members of the MAP kinase family. The observation that activation the p38 MAP kinase and Jun-N-terminal kinase is sensitive to farnesyl protein transferase inhibition raises the possibility that, in addition to cancerous disease, farnesyl protein transferase inhibitors may be useful compounds in combating inflammatory disease.
Vervenne
Walter L
WL
Department of Medical Oncology, Academic Medical Center, Amsterdam, The Netherlands.
Bos
Carina L
CL
Rens
Linda S
LS
Peppelenbosch
Maikel P
MP
Richel
Dick J
DJ
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D004336:Drug Antagonism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051231:Farnesyltranstransferase; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides / Q000494:pharmacology; D008715:Methionine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D004791:Enzyme Inhibitors; C096898:L 744832; D008070:Lipopolysaccharides; D008715:Methionine; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases