Tags

Type your tag names separated by a space and hit enter

SCO2 induces p53-mediated apoptosis by Thr845 phosphorylation of ASK-1 and dissociation of the ASK-1-Trx complex.
Mol Cell Biol. 2013 Apr; 33(7):1285-302.MC

Abstract

p53 prevents cancer via cell cycle arrest, apoptosis, and the maintenance of genome stability. p53 also regulates energy-generating metabolic pathways such as oxidative phosphorylation (OXPHOS) and glycolysis via transcriptional regulation of SCO2 and TIGAR. SCO2, a cytochrome c oxidase assembly factor, is a metallochaperone which is involved in the biogenesis of cytochrome c oxidase subunit II. Here we have shown that SCO2 functions as an apoptotic protein in tumor xenografts, thus providing an alternative pathway for p53-mediated apoptosis. SCO2 increases the generation of reactive oxygen species (ROS) and induces dissociation of the protein complex between apoptosis signal-regulating kinase 1 (ASK-1) (mitogen-activated protein kinase kinase kinase [MAPKKK]) and its cellular inhibitor, the redox-active protein thioredoxin (Trx). Furthermore, SCO2 induces phosphorylation of ASK-1 at the Thr(845) residue, resulting in the activation of the ASK-1 kinase pathway. The phosphorylation of ASK-1 induces the activation of mitogen-activated protein kinase kinases 4 and 7 (MAP2K4/7) and MAP2K3/6, which switches the c-Jun N-terminal protein kinase (JNK)/p38-dependent apoptotic cascades in cancer cells. Exogenous addition of the SCO2 gene to hypoxic cancer cells and hypoxic tumors induces apoptosis and causes significant regression of tumor xenografts. We have thus discovered a novel apoptotic function of SCO2, which activates the ASK-1 kinase pathway in switching "on" an alternate mode of p53-mediated apoptosis. We propose that SCO2 might possess a novel tumor suppressor function via the ROS-ASK-1 kinase pathway and thus could be an important candidate for anticancer gene therapy.

Authors+Show Affiliations

Department of Biochemistry, Chhatrapati Shahuji Maharaj Medical University, Lucknow, India.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23319048

Citation

Madan, Esha, et al. "SCO2 Induces P53-mediated Apoptosis By Thr845 Phosphorylation of ASK-1 and Dissociation of the ASK-1-Trx Complex." Molecular and Cellular Biology, vol. 33, no. 7, 2013, pp. 1285-302.
Madan E, Gogna R, Kuppusamy P, et al. SCO2 induces p53-mediated apoptosis by Thr845 phosphorylation of ASK-1 and dissociation of the ASK-1-Trx complex. Mol Cell Biol. 2013;33(7):1285-302.
Madan, E., Gogna, R., Kuppusamy, P., Bhatt, M., Mahdi, A. A., & Pati, U. (2013). SCO2 induces p53-mediated apoptosis by Thr845 phosphorylation of ASK-1 and dissociation of the ASK-1-Trx complex. Molecular and Cellular Biology, 33(7), 1285-302. https://doi.org/10.1128/MCB.06798-11
Madan E, et al. SCO2 Induces P53-mediated Apoptosis By Thr845 Phosphorylation of ASK-1 and Dissociation of the ASK-1-Trx Complex. Mol Cell Biol. 2013;33(7):1285-302. PubMed PMID: 23319048.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - SCO2 induces p53-mediated apoptosis by Thr845 phosphorylation of ASK-1 and dissociation of the ASK-1-Trx complex. AU - Madan,Esha, AU - Gogna,Rajan, AU - Kuppusamy,Periannan, AU - Bhatt,Madan, AU - Mahdi,Abbas Ali, AU - Pati,Uttam, Y1 - 2013/01/14/ PY - 2013/1/16/entrez PY - 2013/1/16/pubmed PY - 2013/7/31/medline SP - 1285 EP - 302 JF - Molecular and cellular biology JO - Mol Cell Biol VL - 33 IS - 7 N2 - p53 prevents cancer via cell cycle arrest, apoptosis, and the maintenance of genome stability. p53 also regulates energy-generating metabolic pathways such as oxidative phosphorylation (OXPHOS) and glycolysis via transcriptional regulation of SCO2 and TIGAR. SCO2, a cytochrome c oxidase assembly factor, is a metallochaperone which is involved in the biogenesis of cytochrome c oxidase subunit II. Here we have shown that SCO2 functions as an apoptotic protein in tumor xenografts, thus providing an alternative pathway for p53-mediated apoptosis. SCO2 increases the generation of reactive oxygen species (ROS) and induces dissociation of the protein complex between apoptosis signal-regulating kinase 1 (ASK-1) (mitogen-activated protein kinase kinase kinase [MAPKKK]) and its cellular inhibitor, the redox-active protein thioredoxin (Trx). Furthermore, SCO2 induces phosphorylation of ASK-1 at the Thr(845) residue, resulting in the activation of the ASK-1 kinase pathway. The phosphorylation of ASK-1 induces the activation of mitogen-activated protein kinase kinases 4 and 7 (MAP2K4/7) and MAP2K3/6, which switches the c-Jun N-terminal protein kinase (JNK)/p38-dependent apoptotic cascades in cancer cells. Exogenous addition of the SCO2 gene to hypoxic cancer cells and hypoxic tumors induces apoptosis and causes significant regression of tumor xenografts. We have thus discovered a novel apoptotic function of SCO2, which activates the ASK-1 kinase pathway in switching "on" an alternate mode of p53-mediated apoptosis. We propose that SCO2 might possess a novel tumor suppressor function via the ROS-ASK-1 kinase pathway and thus could be an important candidate for anticancer gene therapy. SN - 1098-5549 UR - https://www.unboundmedicine.com/medline/citation/23319048/SCO2_induces_p53_mediated_apoptosis_by_Thr845_phosphorylation_of_ASK_1_and_dissociation_of_the_ASK_1_Trx_complex_ L2 - http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=23319048 DB - PRIME DP - Unbound Medicine ER -