title: A specific defect of prosolin phosphorylation in T cell leukemic lymphoblasts is associated with impaired down-regulation of DNA synthesis.
abstract: Prosolin is a major cytosolic phosphoprotein of proliferating normal PBL. Treatment of growing PBL with phorbol ester (12-O-tetradecanoylphorbol-13-acetate (TPA)) or calcium ionophore (A23187) for 1 h caused phosphorylation of prosolin with the production of up to four prominent phosphorylated forms differing in degree of phosphorylation and/or two-dimensional electrophoretic mobility (peptides B to E). Formation of these phosphopeptides coincided with rapid down-regulation of DNA synthesis. A23187 was particularly effective in inducing phosphorylation of the more highly phosphorylated peptides D and E, suggesting the existence of a (Ca2+)-activated mechanism in their phosphorylation. The T cell leukemia cell lines Jurkat, HuT-78, CCRF-CEM, and Molt-4 showed reduced to absent ability to phosphorylate prosolin peptides rapidly in response to A23187 and also showed diminished down-regulation of DNA synthesis. In leukemic cells treated with both TPA and A23187, peptides B and C were rapidly phosphorylated, but the phosphorylation of peptides D and E seen in normal PBL remained deficient. The T cell leukemic cells appear to have intact a TPA-activated mechanism for phosphorylating prosolin peptides B and C, but share an impairment of a specific Ca2(+)-activated mechanism, possibly a Ca2(+)-dependent protein kinase, required for phosphorylation of prosolin phosphopeptides D and E. The degree of rapid down-regulation of DNA synthesis was correlated with degree of phosphorylation of peptide E in PBL and in three of four T cell leukemic cell lines. Thus, rapid phosphorylation of prosolin may mediate responses to TPA and A23187 in normal proliferating PBL, including down-regulation of DNA synthesis. A deficiency of this pathway in leukemic T cells may impede their response to physiologic growth regulatory signals utilizing this pathway and contribute to unrestrained cell growth.
authors.affiliation: Laboratory of Tumor Immunology and Biology, National Cancer Institute, Bethesda, MD 20892.
authors.forename: H L
authors.initials: HL
authors.lastname: Cooper
authors.forename: R
authors.initials: R
authors.lastname: Fuldner
authors.forename: E
authors.initials: E
authors.lastname: McDuffie
authors.forename: R
authors.initials: R
authors.lastname: Braverman
mesh_terms: D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000502:physiology; D004247:DNA / Q000096:biosynthesis*; D015536:Down-Regulation; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000378:metabolism*; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D009363:Neoplasm Proteins; D010446:Peptide Fragments; D010750:Phosphoproteins; D000001:Calcimycin; D004247:DNA; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium