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Activation of the c-Jun N-terminal kinase (JNK) signaling pathway is essential during PBOX-6-induced apoptosis in chronic myelogenous leukemia (CML) cells.
J Biol Chem. 2002 May 24; 277(21):18383-9.JB

Abstract

The mitogen-activated protein (MAP) kinase family is activated in response to a wide variety of external stress signals such as UV irradiation, heat shock, and many chemotherapeutic drugs and leads to the induction of apoptosis. A novel series of pyrrolo-1,5-benzoxazepines have been shown to potently induce apoptosis in chronic myelogenous leukemia (CML) cells, which are resistant to many chemotherapeutic agents. In this study we have delineated part of the mechanism by which a representative compound known as PBOX-6 induces apoptosis. We have investigated whether PBOX-6 induces activation of MAP kinase signaling pathways in CML cells. Treatment of K562 cells with PBOX-6 resulted in the transient activation of two JNK isoforms, JNK1 and JNK2. In contrast, PBOX-6 did not activate the extracellular signal-regulated kinase (ERK) or p38. Apoptosis was found to occur independently of the small GTPases Ras, Rac, and Cdc42 but involved phosphorylation of the JNK substrates, c-Jun and ATF-2. Pretreatment of K562 cells with the JNK inhibitor, dicoumarol, abolished PBOX-6-induced phosphorylation of c-Jun and ATF-2 and inhibited the induced apoptosis, suggesting that JNK activation is an essential component of the apoptotic pathway induced by PBOX-6. Consistent with this finding, transfection of K562 cells with the JNK scaffold protein, JIP-1, inhibited JNK activity and apoptosis induced by PBOX-6. JIP-1 specifically scaffolds JNK, MKK7, and members of the mixed-lineage kinase (MLK) family, implicating these kinases upstream of JNK in the apoptotic pathway induced by PBOX-6 in K562 cells.

Authors+Show Affiliations

Department of Biochemistry, Trinity College, Dublin 2, Ireland.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11856743

Citation

Mc Gee, Margaret M., et al. "Activation of the c-Jun N-terminal Kinase (JNK) Signaling Pathway Is Essential During PBOX-6-induced Apoptosis in Chronic Myelogenous Leukemia (CML) Cells." The Journal of Biological Chemistry, vol. 277, no. 21, 2002, pp. 18383-9.
Mc Gee MM, Campiani G, Ramunno A, et al. Activation of the c-Jun N-terminal kinase (JNK) signaling pathway is essential during PBOX-6-induced apoptosis in chronic myelogenous leukemia (CML) cells. J Biol Chem. 2002;277(21):18383-9.
Mc Gee, M. M., Campiani, G., Ramunno, A., Nacci, V., Lawler, M., Williams, D. C., & Zisterer, D. M. (2002). Activation of the c-Jun N-terminal kinase (JNK) signaling pathway is essential during PBOX-6-induced apoptosis in chronic myelogenous leukemia (CML) cells. The Journal of Biological Chemistry, 277(21), 18383-9.
Mc Gee MM, et al. Activation of the c-Jun N-terminal Kinase (JNK) Signaling Pathway Is Essential During PBOX-6-induced Apoptosis in Chronic Myelogenous Leukemia (CML) Cells. J Biol Chem. 2002 May 24;277(21):18383-9. PubMed PMID: 11856743.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activation of the c-Jun N-terminal kinase (JNK) signaling pathway is essential during PBOX-6-induced apoptosis in chronic myelogenous leukemia (CML) cells. AU - Mc Gee,Margaret M, AU - Campiani,Giuseppe, AU - Ramunno,Anna, AU - Nacci,Vito, AU - Lawler,Mark, AU - Williams,D Clive, AU - Zisterer,Daniela M, Y1 - 2002/02/20/ PY - 2002/2/22/pubmed PY - 2002/6/25/medline PY - 2002/2/22/entrez SP - 18383 EP - 9 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 277 IS - 21 N2 - The mitogen-activated protein (MAP) kinase family is activated in response to a wide variety of external stress signals such as UV irradiation, heat shock, and many chemotherapeutic drugs and leads to the induction of apoptosis. A novel series of pyrrolo-1,5-benzoxazepines have been shown to potently induce apoptosis in chronic myelogenous leukemia (CML) cells, which are resistant to many chemotherapeutic agents. In this study we have delineated part of the mechanism by which a representative compound known as PBOX-6 induces apoptosis. We have investigated whether PBOX-6 induces activation of MAP kinase signaling pathways in CML cells. Treatment of K562 cells with PBOX-6 resulted in the transient activation of two JNK isoforms, JNK1 and JNK2. In contrast, PBOX-6 did not activate the extracellular signal-regulated kinase (ERK) or p38. Apoptosis was found to occur independently of the small GTPases Ras, Rac, and Cdc42 but involved phosphorylation of the JNK substrates, c-Jun and ATF-2. Pretreatment of K562 cells with the JNK inhibitor, dicoumarol, abolished PBOX-6-induced phosphorylation of c-Jun and ATF-2 and inhibited the induced apoptosis, suggesting that JNK activation is an essential component of the apoptotic pathway induced by PBOX-6. Consistent with this finding, transfection of K562 cells with the JNK scaffold protein, JIP-1, inhibited JNK activity and apoptosis induced by PBOX-6. JIP-1 specifically scaffolds JNK, MKK7, and members of the mixed-lineage kinase (MLK) family, implicating these kinases upstream of JNK in the apoptotic pathway induced by PBOX-6 in K562 cells. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/11856743/Activation_of_the_c_Jun_N_terminal_kinase__JNK__signaling_pathway_is_essential_during_PBOX_6_induced_apoptosis_in_chronic_myelogenous_leukemia__CML__cells_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=11856743 DB - PRIME DP - Unbound Medicine ER -