title: Mitochondrial targeting of JNK/SAPK in the phorbol ester response of myeloid leukemia cells.
abstract: Treatment of human U-937 myeloid leukemia cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) is associated with activation of the stress-activated protein kinase (SAPK) and induction of terminal monocytic differentiation. The present studies demonstrate that TPA targets SAPK to mitochondria by a mechanism dependent on activation of protein kinase C (PKC) beta. Translocation of SAPK to mitochondria in response to TPA is associated with release of cytochrome c, caspase-3 activation and induction of apoptosis. The results show that TPA induces the association of SAPK with the mitochondrial anti-apoptotic Bcl-x(L) protein. Overexpression of Bcl-x(L) attenuated the apoptotic response to TPA treatment. Moreover, expression of Bcl-x(L) mutated at sites of SAPK phosphorylation (Thr-47, -115) was more effective than wild-type Bcl-x(L) in abrogating TPA-induced cytochrome c release and apoptosis. By contrast, expression of Bcl-x(L) had little effect on induction of the monocytic phenotype. These findings indicate that myeloid leukemia cells respond to TPA with targeting of SAPK to mitochondria and that this response contributes to terminal differentiation through the release of cytochrome c and induction of apoptosis.
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Ito
authors.forename: N C
authors.initials: NC
authors.lastname: Mishra
authors.forename: K
authors.initials: K
authors.lastname: Yoshida
authors.forename: S
authors.initials: S
authors.lastname: Kharbanda
authors.forename: S
authors.initials: S
authors.lastname: Saxena
authors.forename: D
authors.initials: D
authors.lastname: Kufe
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002273:Carcinogens / Q000494:pharmacology; D002451:Cell Compartmentation / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D003574:Cytochrome c Group / Q000187:drug effects / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D015151:Immunoblotting; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D064546:Protein Kinase C beta; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051020:bcl-X Protein
chemical_list: C494811:BCL2L1 protein, human; D002273:Carcinogens; D003574:Cytochrome c Group; D007527:Isoenzymes; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate