title: Role of WW Domain-containing Oxidoreductase WWOX in Driving T Cell Acute Lymphoblastic Leukemia Maturation.
abstract: Whether tumor suppressor WWOX (WW domain-containing oxidoreductase) stimulates immune cell maturation is largely unknown. Here, we determined that Tyr-33-phosphorylated WWOX physically binds non-phosphorylated ERK and IκBα in immature acute lymphoblastic leukemia MOLT-4 T cells and in the naïve mouse spleen. The IκBα·ERK·WWOX complex was shown to localize, in part, in the mitochondria. WWOX prevents IκBα from proteasomal degradation. Upon stimulating MOLT-4 with ionophore A23187/phorbol myristate acetate, endogenous IκBα and ERK undergo rapid phosphorylation in <5 min, and subsequently WWOX is Tyr-33 and Tyr-287 de-phosphorylated and Ser-14 phosphorylated. Three hours later, IκBα starts to degrade, and ERK returns to basal or non-phosphorylation, and this lasts for the next 12 h. Finally, expression of CD3 and CD8 occurs in MOLT-4 along with reappearance of the IκBα·ERK·WWOX complex near 24 h. Inhibition of ERK phosphorylation by U0126 or IκBα degradation by MG132 prevents MOLT-4 maturation. By time-lapse FRET microscopy, IκBα·ERK·WWOX complex exhibits an increased binding strength by 1-2-fold after exposure to ionophore A23187/phorbol myristate acetate for 15-24 h. Meanwhile, a portion of ERK and WWOX relocates to the nucleus, suggesting their role in the induction of CD3 and CD8 expression in MOLT-4.
authors.affiliation: From the Institute of Molecular Medicine.
authors.forename: Shenq-Shyang
authors.initials: SS
authors.lastname: Huang
authors.affiliation: From the Institute of Molecular Medicine.
authors.forename: Wan-Pei
authors.initials: WP
authors.lastname: Su
authors.affiliation: From the Institute of Molecular Medicine.
authors.forename: Hsin-Pin
authors.initials: HP
authors.lastname: Lin
authors.affiliation: From the Institute of Molecular Medicine.
authors.forename: Hsiang-Ling
authors.initials: HL
authors.lastname: Kuo
authors.affiliation: From the Institute of Molecular Medicine.
authors.forename: Hsiao-Ling
authors.initials: HL
authors.lastname: Wei
authors.affiliation: From the Institute of Molecular Medicine, Center of Infectious Disease and Signaling Research, and Advanced Optoelectronic Technology Center, National Cheng Kung University, Tainan 70101, Taiwan, Republic of China, Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, New York 10314, Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, New York 13210, Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 40402, Taiwan, Republic of China nschang13827@gmail.com.
authors.forename: Nan-Shan
authors.initials: NS
authors.lastname: Chang
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha / Q000235:genetics / Q000378:metabolism; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000072417:Protein Domains; D059748:Proteolysis / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D020298:U937 Cells; D000074584:WW Domain-Containing Oxidoreductase
chemical_list: D046912:Multiprotein Complexes; D025521:Tumor Suppressor Proteins; D000072000:NF-KappaB Inhibitor alpha; D000001:Calcimycin; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human; C428130:Wwox protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D013755:Tetradecanoylphorbol Acetate
keywords: differentiation; extracellular-signal-regulated kinase (ERK); lymphocyte; phorbol ester; phosphorylation; tumor suppressor gene