Parathyroid hormone induction of creatine kinase activity and DNA synthesis is mimicked by phospholipase C, diacylglycerol and phorbol ester.
Parathyroid hormone (PTH), which increases cAMP levels, also induces an increase in the activity of the brain isozyme of creatine kinase and in DNA synthesis in osteoblast-enriched bone cell cultures by a cAMP-independent mechanism. The following results lead us to the conclusion that PTH induction of brain isozyme of creatine kinase activity and DNA synthesis occurs by activation of membranal phospholipid metabolism leading to increased protein kinase C activity and Ca2+ mobilization, a mechanism demonstrated for several growth factors and other hormones. (1) Binding of membranal phospholipids by agents such as gentamycin or antiphospholipid antibodies abolishes the stimulation by PTH of creatine kinase activity and DNA synthesis but not of cAMP production. (2) Treatment of cell cultures with exogenous phospholipase C increases brain isozyme of creatine kinase activity and DNA synthesis, but not cAMP production; these stimulations are also blocked by serum containing anti-phospholipid antibodies. PTH has no additional effect on stimulation of creatine kinase activity by phospholipase C (and only a slight effect on DNA synthesis). (3) A synthetic diacylglycerol (1-oleyl-2-acetyl glycerol) or phorbol ester (phorbol 12-myristate 13-acetate) or Ca2+ ionophore, A23187 induces creatine kinase activity and DNA synthesis in the cultures. However, this effect is not blocked by antiphospholipid sera and PTH has no additional effect. (4) Inhibition of protein kinase C activity by drugs reported to inhibit the enzyme (retinoic acid, quercetin) abolishes the stimulation of brain isozyme of creatine kinase activity and of DNA synthesis by PTH.
Sömjen
D
D
Hard Tissues Unit, Ichilov Hospital, Tel Aviv Medical Center, Israel.
Zor
U
U
Kaye
A M
AM
Harell
A
A
Binderman
I
I
D000818:Animals; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism*; D002116:Calcitonin / Q000494:pharmacology; D002478:Cells, Cultured; D003402:Creatine Kinase / Q000096:biosynthesis*; D000242:Cyclic AMP / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects*; D004075:Diglycerides / Q000494:pharmacology*; D004622:Embryo, Mammalian; D004790:Enzyme Induction; D005989:Glycerides / Q000494:pharmacology*; D010281:Parathyroid Hormone / Q000494:pharmacology*; D011794:Quercetin / Q000494:pharmacology; D051381:Rats; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000494:pharmacology*
D004075:Diglycerides; D005989:Glycerides; D010281:Parathyroid Hormone; C038237:1-oleoyl-2-acetylglycerol; D002116:Calcitonin; D011794:Quercetin; D000242:Cyclic AMP; D003402:Creatine Kinase; D010738:Type C Phospholipases; D013755:Tetradecanoylphorbol Acetate