title: Myeloid cell leukemia 1 is phosphorylated through two distinct pathways, one associated with extracellular signal-regulated kinase activation and the other with G2/M accumulation or protein phosphatase 1/2A inhibition.
abstract: Protein kinase C activators and microtubule-damaging drugs stimulate BCL2 phosphorylation, which has been associated with either enhancement or inhibition of cell viability. In a Burkitt lymphoma cell line, both types of agents likewise stimulated phosphorylation of myeloid cell leukemia 1 (MCL1), another viability-promoting BCL2 family member. However, while MCL1 phosphorylation induced by the protein kinase C activator, 12-O-tetradecanoylphorbol-13-acetate (TPA), did not affect its electrophoretic mobility, microtubule-damaging agents, such as taxol, induced MCL1 phosphorylation associated with a band shift to decreased mobility. Inhibitors of extracellular signal-regulated kinase (ERK) activation blocked TPA-induced MCL1 phosphorylation but not the taxol-induced band shift. TPA-induced MCL1 phosphorylation occurred rapidly and was not associated with decreased viability, while the taxol-induced band shift occurred upon extended exposure as cells accumulated in G(2)/M followed by cell death. Protein phosphatase 1/2A inhibitors also induced the MCL1 band shift/phosphorylation. Thus, MCL1 undergoes two distinct types of phosphorylation: (i) TPA-induced, ERK-associated phosphorylation, which does not alter the electrophoretic mobility of MCL1, and (ii) ERK-independent phosphorylation, which results in an MCL1 band shift and is induced by events in G(2)/M or protein phosphatase 1/2A inhibitors.
authors.affiliation: Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Domina
authors.forename: J H
authors.initials: JH
authors.lastname: Smith
authors.forename: R W
authors.initials: RW
authors.lastname: Craig
mesh_terms: D002051:Burkitt Lymphoma; D002453:Cell Cycle / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016195:G2 Phase; D006801:Humans; D008387:Marine Toxins; D008870:Microtubules / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008938:Mitosis; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000302:isolation & purification / Q000378:metabolism*; D015739:Nocodazole / Q000494:pharmacology; D019319:Okadaic Acid / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D008387:Marine Toxins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D010080:Oxazoles; D019253:Proto-Oncogene Proteins c-bcl-2; D019319:Okadaic Acid; D014747:Vinblastine; C059041:calyculin A; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases; D013755:Tetradecanoylphorbol Acetate; D017239:Paclitaxel; D015739:Nocodazole