title: p53-mediated activation of the mitochondrial protease HtrA2/Omi prevents cell invasion.
abstract: Oncogenic Ras induces cell transformation and promotes an invasive phenotype. The tumor suppressor p53 has a suppressive role in Ras-driven invasion. However, its mechanism remains poorly understood. Here we show that p53 induces activation of the mitochondrial protease high-temperature requirement A2 (HtrA2; also known as Omi) and prevents Ras-driven invasion by modulating the actin cytoskeleton. Oncogenic Ras increases accumulation of p53 in the cytoplasm, which promotes the translocation of p38 mitogen-activated protein kinase (MAPK) into mitochondria and induces phosphorylation of HtrA2/Omi. Concurrently, oncogenic Ras also induces mitochondrial fragmentation, irrespective of p53 expression, causing the release of HtrA2/Omi from mitochondria into the cytosol. Phosphorylated HtrA2/Omi therefore cleaves β-actin and decreases the amount of filamentous actin (F-actin) in the cytosol. This ultimately down-regulates p130 Crk-associated substrate (p130Cas)-mediated lamellipodia formation, countering the invasive phenotype initiated by oncogenic Ras. Our novel findings provide insights into the mechanism by which p53 prevents the malignant progression of transformed cells.
authors.affiliation: Mechanobiology Institute, Level 10, T-Lab, National University of Singapore, Singapore 117411, Singapore.
authors.forename: Shota
authors.initials: S
authors.lastname: Yamauchi
authors.forename: Yan Yan
authors.initials: YY
authors.lastname: Hou
authors.forename: Alvin Kunyao
authors.initials: AK
authors.lastname: Guo
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Hirata
authors.forename: Wataru
authors.initials: W
authors.lastname: Nakajima
authors.forename: Ai Kia
authors.initials: AK
authors.lastname: Yip
authors.forename: Cheng-han
authors.initials: CH
authors.lastname: Yu
authors.forename: Ichiro
authors.initials: I
authors.lastname: Harada
authors.forename: Keng-Hwee
authors.initials: KH
authors.lastname: Chiam
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Sawada
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Tanaka
authors.forename: Keiko
authors.initials: K
authors.lastname: Kawauchi
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D050719:Crk-Associated Substrate Protein / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation; D057809:HEK293 Cells; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000201:enzymology; D024101:Mitochondrial Proteins / Q000378:metabolism*; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D059748:Proteolysis; D011554:Pseudopodia / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*; D059010:Single-Cell Analysis; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D000199:Actins; C493842:Bcar1 protein, mouse; D050719:Crk-Associated Substrate Protein; D024101:Mitochondrial Proteins; D016159:Tumor Suppressor Protein p53; D048051:p38 Mitogen-Activated Protein Kinases; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse; D018631:ras Proteins