Cross-talk between protein kinase C-alpha (PKC-alpha) and -delta (PKC-delta): PKC-alpha elevates the PKC-delta protein level, altering its mRNA transcription and degradation.
Studies utilizing the overexpression of individual isoforms indicated that both PKC-alpha and -delta promote a number of biological effects, including inhibition of DNA synthesis associated with rearrangements of the actin cytoskeleton in the murine B-cell lymphoma (Baf3), differentiation of the murine promyelocyte line 32D, and activation of MAP kinase in CHO fibroblasts. We postulated that these results reflect some form of cross-regulation between PKC-alpha and -delta rather than their functional redundancy. In this report, we show that overexpression of PKC-alpha in Baf3 and 32D leads to an elevation of the endogenous PKC-delta mRNA and protein levels. The elevated steady-state PKC-delta mRNA level results from a combination of increased PKC-delta transcription and mRNA stability. Upregulation of PKC-delta mRNA by PKC-alpha occurs even after a selective depletion of the PKC-delta protein. In addition, phorbol ester-induced elevation of PKC-delta mRNA and protein levels can be prevented by the PKC inhibitor GF109203X, an indication of the requirement for PKC kinase activity. Inhibition of new protein synthesis by cycloheximide showed that upregulation of PKC-delta mRNA, as opposed to delayed downregulation of the PKC-delta protein, is primarily responsible for the accumulation of this isoform by PKC-alpha. In parental Baf3 and 32D cells and PKC-alpha overexpressers, PKC-alpha and PKC-delta are uniquely involved in cross-regulation, while PKC-epsilon, PKC-eta, and PKC-mu are not.
Romanova
L Y
LY
Laboratory of Genetics and Medicine Branch, National Cancer Institute, Bethesda, Maryland 20892, USA.
Alexandrov
I A
IA
Nordan
R P
RP
Blagosklonny
M V
MV
Mushinski
J F
JF
D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D004795:Enzyme Stability / Q000187:drug effects / Q000235:genetics; D007211:Indoles / Q000494:pharmacology; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D015473:Leukemia, Promyelocytic, Acute; D016393:Lymphoma, B-Cell; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D011493:Protein Kinase C / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D012333:RNA, Messenger / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D007211:Indoles; D007527:Isoenzymes; D008301:Maleimides; D012333:RNA, Messenger; C497259:Prkcd protein, mouse; C496630:Prkca protein, mouse; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; C070515:bisindolylmaleimide I; D013755:Tetradecanoylphorbol Acetate