Molecular basis of alpha-tocopherol control of smooth muscle cell proliferation.
Rat and human vascular smooth muscle cell proliferation is specifically sensitive to alpha-tocopherol, but not beta-tocopherol. The former, but not the latter, is capable of limiting proliferation and inhibiting protein kinase C activity in a dose-dependent manner. The phenomenon occurs at concentrations in the range 10-50 microM. beta-tocopherol addition together with alpha-tocopherol, prevents both cell growth and protein kinase C inhibition. alpha-tocopherol increases de novo synthesis of protein kinase C molecules. The enzyme specific activity, however, is diminished, due to a decreased phosphorylation of protein kinase C, occurring in the presence of alpha-tocopherol. Experiments with protein kinase C isoform-specific inhibitors and precipitating antibodies show that the only isoform affected by alpha-tocopherol is protein kinase C-alpha. The effect of alpha-tocopherol is prevented by okadaic acid indicating a phosphatase of the PP2A type as responsible for protein kinase C-alpha dephosphorylation produced in the presence of alpha-tocopherol. At a gene level alpha-tocopherol but not beta-tocopherol induces a transient activation of alpha-tropomyosin gene transcription and protein expression. It is proposed that, by inhibiting protein kinase C activity via an activation of a phosphatase PP2A, alpha-tocopherol controls smooth muscle cell proliferation through changes in gene expression.
Azzi
A
A
Institut für Biochemie und Molekularbiologie, Universität Bern, Switzerland.
Aratri
E
E
Boscoboinik
D
D
Clément
S
S
Ozer
N K
NK
Ricciarelli
R
R
Spycher
S
S
D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007163:Immunosorbent Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D009130:Muscle, Smooth / Q000166:cytology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D010766:Phosphorylation; D011471:Prostatic Neoplasms; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D014335:Tropomyosin / Q000235:genetics; D014407:Tumor Cells, Cultured; D014810:Vitamin E / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D014335:Tropomyosin; D014810:Vitamin E; D011493:Protein Kinase C