Nan-Shan Chang
National Cheng Kung University, Taiwan
Title: Role of WW domain-containing oxidoreductase WWOX in driving T-cell acute lymphoblastic leukemia maturationï€ Role of WW domain-containing oxidoreductase WWOX in driving T-cell acute lymphoblastic leukemia maturation
Biography
Biography: Nan-Shan Chang
Abstract
Whether tumor suppressor WWOX stimulates immune cell maturation is largely unknown. Here, we determined that Tyr33-phosphorylated WWOX physically binds non-phosphorylated ERK and IκBα in immature acute lymphoblastic leukemia MOLT-4 T cell and in the naïve mouse spleen. The IκBα/ERK/WWOX complex was shown to localize, in part, in the mitochondria. WWOX prevents IκBα from proteosomal degradation. Upon stimulating MOLT-4 with ionophore A23187/phorbol myristate acetate (IoP), endogenous IκBα and ERK undergo rapid phosphorylation in less than 5 min, and subsequently WWOX is Tyr33 and Tyr287 de-phosphorylated and Ser14 phosphorylated. Three hr later, IκBα starts to degrade and ERK returns to basal or non-phosphorylation, and this lasts in the next 12 hr. Finally, expression of CD3 and CD8 occurs in MOLT-4, along with re-appearance of the IκBα/ERK/WWOX complex near 24 hr. 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 IoP for 15-24 hrs. Meanwhile, a portion of ERK and WWOX relocate to the nucleus, suggesting their role in the induction of CD3 and CD8 expression in MOLT-4. (Supported by MOST and NHRI, Taiwan, and DoD, USA)