Browsing by Author "Lee, Brendan"

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    The Crucial p53-Dependent Oncogenic Role of JAB1 in Osteosarcoma in vivo
    (Nature, 2020-06) Samsa, William E.; Mamidi, Murali K.; Bashur, Lindsay A.; Elliott, Robin; Miron, Alexander; Chen, Yuqing; Lee, Brendan; Greenfield, Edward M.; Chan, Ricky; Danielpour, David; Zhou, Guang; Orthopaedic Surgery, School of Medicine
    Osteosarcoma (OS) is the most common primary bone cancer and ranks amongst the leading causes of cancer mortality in young adults. Jun activation domain binding protein 1 (JAB1) is overexpressed in many cancers and has recently emerged as a novel target for cancer treatment. However, the role of JAB1 in osteosarcoma was virtually unknown. In this study, we demonstrate that JAB1-knockdown in malignant osteosarcoma cell lines significantly reduced their oncogenic properties, including proliferation, colony formation, and motility. We also performed RNA-sequencing analysis in JAB1-knockdown OS cells and identified 4110 genes that are significantly differentially expressed. This demonstrated for the first time that JAB1 regulates a large and specific transcriptome in cancer. We also found that JAB1 is overexpressed in human OS and correlates with a poor prognosis. Moreover, we generated a novel mouse model that overexpresses Jab1 specifically in osteoblasts upon a TP53 heterozygous sensitizing background. Interestingly, by 13 months of age, a significant proportion of these mice spontaneously developed conventional OS. Finally, we demonstrate that a novel, highly specific small molecule inhibitor of JAB1, CSN5i-3, reduces osteosarcoma cell viability and has specific effects on the ubiquitin-proteasome system in OS. Thus, we show for the first time that the overexpression of JAB1 in vivo can result in accelerated spontaneous tumor formation in a p53-dependent manner. In summary, JAB1 might be a unique target for the treatment of osteosarcoma and other cancers.
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    Pathogenic Variants in Fucokinase Cause a Congenital Disorder of Glycosylation
    (Elsevier, 2018-12-06) Ng, Bobby G.; Rosenfeld, Jill A.; Emrick, Lisa; Jain, Mahim; Burrage, Lindsay C.; Lee, Brendan; Craigen, William J.; Bearden, David R.; Graham, Brett H.; Freeze, Hudson H.; Medical and Molecular Genetics, School of Medicine
    FUK encodes fucokinase, the only enzyme capable of converting L-fucose to fucose-1-phosphate, which will ultimately be used for synthesizing GDP-fucose, the donor substrate for all fucosyltransferases. Although it is essential for fucose salvage, this pathway is thought to make only a minor contribution to the total amount of GDP-fucose. A second pathway, the major de novo pathway, involves conversion of GDP-mannose to GDP-fucose. Here we describe two unrelated individuals who have pathogenic variants in FUK and who presented with severe developmental delays, encephalopathy, intractable seizures, and hypotonia. The first individual was compound heterozygous for c.667T>C (p.Ser223Pro) and c.2047C>T (p.Arg683Cys), and the second individual was homozygous for c.2980A>C (p.Lys994Gln). Skin fibroblasts from the first individual confirmed the variants as loss of function and showed significant decreases in total GDP-[3H] fucose and [3H] fucose-1-phosphate. There was also a decrease in the incorporation of [5,6-3H]-fucose into fucosylated glycoproteins. Lys994 has previously been shown to be an important site for ubiquitin conjugation. Here, we show that loss-of-function variants in FUK cause a congenital glycosylation disorder characterized by a defective fucose-salvage pathway.
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    Phenotypic expansion in DDX3X - a common cause of intellectual disability in females
    (Wiley, 2018-09-15) Wang, Xia; Posey, Jennifer E.; Rosenfeld, Jill A.; Bacino, Carlos A.; Scaglia, Fernando; Immken, LaDonna; Harris, Jill M.; Hickey, Scott E.; Mosher, Theresa M.; Slavotinek, Anne; Zhang, Jing; Beuten, Joke; Leduc, Magalie S.; He, Weimin; Vetrini, Francesco; Walkiewicz, Magdalena A.; Bi, Weimin; Xiao, Rui; Liu, Pengfei; Shao, Yunru; Gezdirici, Alper; Gulec, Elif Y.; Jiang, Yunyun; Darilek, Sandra A.; Hansen, Adam W.; Khayat, Michael M.; Pehlivan, Davut; Piard, Juliette; Muzny, Donna M.; Hanchard, Neil; Belmont, John W.; Van Maldergem, Lionel; Gibbs, Richard A.; Eldomery, Mohammad K.; Akdemir, Zeynep C.; Adesina, Adekunle M.; Chen, Shan; Lee, Yi-Chien; Lee, Brendan; Lupski, James R.; Eng, Christine M.; Xia, Fan; Yang, Yaping; Graham, Brett H.; Moretti, Paolo; Medical and Molecular Genetics, School of Medicine
    De novo variants in DDX3X account for 1-3% of unexplained intellectual disability (ID) cases and are amongst the most common causes of ID especially in females. Forty-seven patients (44 females, 3 males) have been described. We identified 31 additional individuals carrying 29 unique DDX3X variants, including 30 postnatal individuals with complex clinical presentations of developmental delay or ID, and one fetus with abnormal ultrasound findings. Rare or novel phenotypes observed include respiratory problems, congenital heart disease, skeletal muscle mitochondrial DNA depletion, and late-onset neurologic decline. Our findings expand the spectrum of DNA variants and phenotypes associated with DDX3X disorders.