Browsing by Author "Zhou, Qi"

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    Immunotoxin SS1P is rapidly removed by proximal tubule cells of kidney, whose damage contributes to albumin loss in urine
    (National Academy of Sciences, 2020-03-02) Liu, Xui-Fen; Wei, Junxia; Zhou, Qi; Molitoris, Bruce A.; Sandoval, Ruben; Kobayashi, Hisataka; Okada, Ryuhei; Nagaya, Tadanobu; Karim, Baktiar; Butcher, Donna; Pastan, Ira; Medicine, School of Medicine
    Recombinant immunotoxins (RITs) are chimeric proteins composed of an Fv and a protein toxin being developed for cancer treatment. The Fv brings the toxin to the cancer cell, but most of the RITs do not reach the tumor and are removed by other organs. To identify cells responsible for RIT removal, and the pathway by which RITs reach these cells, we studied SS1P, a 63-kDa RIT that targets mesothelin-expressing tumors and has a short serum half-life. The major organs that remove RIT were identified by live mouse imaging of RIT labeled with FNIR-Z-759. Cells responsible for SS1P removal were identified by immunohistochemistry and intravital two-photon microscopy of kidneys of rats. The primary organ of SS1P removal is kidney followed by liver. In the kidney, SS1P passes through the glomerulus, is taken up by proximal tubular cells, and transferred to lysosomes. In the liver, macrophages are involved in removal. The short half-life of SS1P is due to its very rapid filtration by the kidney followed by degradation in proximal tubular cells of the kidney. In mice treated with SS1P, proximal tubular cells are damaged and albumin in the urine is increased. SS1P uptake by kidney is reduced by coadministration of l-lysine. Our data suggests that l-lysine administration to humans might prevent SS1P-mediated kidney damage, reduce albumin loss in urine, and alleviate capillary leak syndrome.
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    Protein phosphatase 5 and the tumor suppressor p53 down-regulate each other's activities in mice
    (American Society for Biochemistry and Molecular Biology, 2018-11-23) Wang, Jun; Shen, Tao; Zhu, Wuqiang; Dou, Longyu; Gu, Hao; Zhang, Lingling; Yang, Zhenyun; Chen, Hanying; Zhou, Qi; Sánchez, Edwin R.; Field, Loren J.; Mayo, Lindsey D.; Xie, Zhongwen; Xiao, Deyong; Lin, Xia; Shou, Weinian; Yong, Weidong; Pediatrics, School of Medicine
    Protein phosphatase 5 (PP5), a serine/threonine phosphatase, has a wide range of biological functions and exhibits elevated expression in tumor cells. We previously reported that pp5-deficient mice have altered ataxia-telangiectasia mutated (ATM)-mediated signaling and function. However, this regulation was likely indirect, as ATM is not a known PP5 substrate. In the current study, we found that pp5-deficient mice are hypersensitive to genotoxic stress. This hypersensitivity was associated with the marked up-regulation of the tumor suppressor tumor protein p53 and its downstream targets cyclin-dependent kinase inhibitor 1A (p21), MDM2 proto-oncogene (MDM2), and phosphatase and tensin homolog (PTEN) in pp5-deficient tissues and cells. These observations suggested that PP5 plays a role in regulating p53 stability and function. Experiments conducted with p53 +/- pp5 +/- or p53 +/- pp5 -/- mice revealed that complete loss of PP5 reduces tumorigenesis in the p53 +/- mice. Biochemical analyses further revealed that PP5 directly interacts with and dephosphorylates p53 at multiple serine/threonine residues, resulting in inhibition of p53-mediated transcriptional activity. Interestingly, PP5 expression was significantly up-regulated in p53-deficient cells, and further analysis of pp5 promoter activity revealed that p53 strongly represses PP5 transcription. Our results suggest a reciprocal regulatory interplay between PP5 and p53, providing an important feedback mechanism for the cellular response to genotoxic stress.