Tyrosine kinases but not cAMP-dependent protein kinase mediate the induction of leukocyte alkaline phosphatase by granulocyte-colony-stimulating factor and retinoic acid in acute promyelocytic leukemia cells.
Leukocyte alkaline phosphatase (LAP) is synergistically induced by the combination of all-trans retinoic acid (ATRA) and granulocyte-colony-stimulating factor (G-CSF) in acute promyelocytic leukemia (APL) cells (Gianni' M. et al., Blood 83: 1909-1921, 1994). The role of cAMP and tyrosine kinases in the induction of LAP was investigated. In the APL cell line NB4, adenosine-3': 5'-monophosphothioate, cyclic, Rp isomer, a reversible inhibitor of cAMP-dependent protein kinase (PKA), has no effect on the induction of LAP enzymatic activity and mRNA triggered by ATRA+G-CSF, in conditions where this compound completely blocks the upregulation of LAP transcript caused by the combination of the PKA agonist, dibutyryl-cAMP (db-cAMP), and ATRA. Challenge of NB4 cells with G-CSF, dbcAMP and ATRA causes a much higher induction of LAP relative to that observed in the presence of ATRA+G-CSF or ATRA+dbcAMP. Treatment of NB4 with ATRA and G-CSF results in increases in the tyrosine phosphorylation of several proteins. In the presence of the cytokine and the retinoid, tyrosine kinase inhibitors decrease LAP enzymatic activity and mRNA.
Gianni
M
M
Molecular Biology Unit, Centro Catullo e Daniela Borgomanierio, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
Li Calzi
M
M
Terao
M
M
Rambaldi
A
A
Garattini
E
E
D000469:Alkaline Phosphatase / Q000378:metabolism*; D003994:Bucladesine / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019833:Genistein; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D066298:In Vitro Techniques; D007529:Isoflavones / Q000494:pharmacology; D015473:Leukemia, Promyelocytic, Acute / Q000201:enzymology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000235:genetics; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D006873:Hydroquinones; D007529:Isoflavones; D012334:RNA, Neoplasm; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016179:Granulocyte Colony-Stimulating Factor; D014212:Tretinoin; D003994:Bucladesine; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D000469:Alkaline Phosphatase; C048212:erbstatin