SCO2 induces p53-mediated apoptosis by Thr845 phosphorylation of ASK-1 and dissociation of the ASK-1-Trx complex.

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: Esha Madan, Rajan Gogna, Periannan Kuppusamy, Madan Bhatt, Abbas Ali Mahdi, Uttam Pati
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 33 Issue 7 Pg. 1285-302 (Apr 2013) ISSN: 1098-5549 [Electronic] United States
• PMID: 23319048 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• Intracellular Signaling Peptides and Proteins
• Membrane Proteins
• Mitochondrial Proteins
• Molecular Chaperones
• Reactive Oxygen Species
• SCO2 protein, human
• TP53 protein, human
• Tumor Suppressor Protein p53
• VAC14 protein, human
• JNK Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• MAP Kinase Kinase Kinase 5
• MAP3K5 protein, human
• Mitogen-Activated Protein Kinase Kinases

Topics

• Apoptosis (physiology)
• Carrier Proteins (genetics, metabolism)
• Cell Line, Tumor
• Humans
• Intracellular Signaling Peptides and Proteins
• JNK Mitogen-Activated Protein Kinases (genetics, metabolism)
• MAP Kinase Kinase Kinase 5 (genetics, metabolism)
• MCF-7 Cells
• Membrane Proteins (genetics, metabolism)
• Mitochondrial Proteins (genetics, metabolism)
• Mitogen-Activated Protein Kinase Kinases (genetics, metabolism)
• Molecular Chaperones
• Phosphorylation
• Reactive Oxygen Species (metabolism)
• Signal Transduction (genetics)
• Tumor Suppressor Protein p53 (genetics, metabolism)
• p38 Mitogen-Activated Protein Kinases (genetics, metabolism)