Characterizing the functional role of
WWOX in thymocyte development
Tsung-Hao Chang
Institute of Basic Medical Sciences,
WW domain-containing oxidoreductase (WWOX) serves as a candidate tumor suppressor
Reduced expression • Breast cancer • Ovarian cancer • Prostate cancer • Liver cancer • Gastric cancer • Osteosarcoma • Hematopoietic malignancies Loss of hetero-zygosity • Breast cancer • Gastric cancer • Childhood cancers Hyper-methylated promoter • Breast cancer • Ovarian cancer • Prostate cancer • Hematopoietic malignancies • Childhood cancers
WWOX deficiency results in severe neuronal and immune
disorders in human and animal models
Epileptic encephalopathy:
• WWOX and severe autosomal recessive epileptic encephalopathy: first case in the prenatal period
J Hum Genet. 2015 May;60(5):267-71
• A spontaneous mutation of the Wwox gene and audiogenic seizures in rats with
lethal dwarfism and epilepsy
Genes Brain Behav. 2009 Oct;8(7):650-60
Immune disorder:
• Generation and characterization of mice carrying a conditional allele of the Wwox
tumor suppressor gene
A. B. C.
D.
Severe thymic atrophy and developmental defects in
A. TU N EL tiv e c as pa se -3 B. C.
Experimental Design
+/+ or -/-
Bone marrow cells
CD45.2+
transfer NOD.SCID mice
T- and B-cell deficiency
CD45.1+
Wwox-/- thymocytes have intrinsic defects in differentiation
Notch1 +/+ +/- -/- A. B. C.
Notch1 protein expression is down-regulated in Wwox-/-
thymocytes
D.
β-actin Notch1
ITCH negatively regulates NOTCH1 expression through promoting NOTCH1 ubiquitination
ARRDC1 NOTCH1 WW HECT C2 WW WW WW PPXY PPXY
A. B.
A. B.
WWOX downregulates ITCH expression through promoting its K48-ubiquitination
A.
C. D.
B.
WWOX interacts with N-terminus of ICN through N-terminal WW domains and C-terminal SDR domain
A. B. C.
WWOX interacts with NOTCH1 to block the binding of NOTCH1 to E3 ligase ITCH
Summary
Wwox-/-
Wwox+/+
1. 2.
Acknowledgements Dr. Li-Jin Hsu Jui-Yen Lo Hui-Ching Cheng Ying-Tsen Chou Po-Chih Hsu Yung-Tsai Liou Ya-Yun Cheng Tsung-Chih Huang Kai-Fei Chang Shao-Han Liao Yu-Han Su NaBonal Cheng Kung University
