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Zhu, Cheng

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Zhu, Cheng

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2008 - 200912010 - 20111

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Author's Publications: search.filters.isAuthorOfPublication.eeb06d51-e9c3-4f9a-a4ce-9e82c7f72e03

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    Protein Tyrosine Phosphatase-1B (PTP1B) Helps Regulate EGF-induced Stimulation of S-phase Entry in Human Corneal Endothelial Cells
    (Molecular Vision, 2008) Ishino, Yutaka; Zhu, Cheng; Harris, Deshea L.; Joyce, Nancy C.
    Purpose: Human corneal endothelial cells (HCEC), particularly from older donors, only proliferate weakly in response to EGF. The protein tyrosine phosphatase, PTP1B, is known to negatively regulate EGF-induced signaling in several cell types by dephosphorylating the epidermal growth factor receptor (EGFR). The current studies were conducted to determine whether PTP1B plays a role in regulating cell cycle entry in HCEC in response to EGF stimulation. Methods: Donor corneas were obtained from the National Disease Research Interchange and accepted for study based on established exclusion criteria. PTP1B was localized in the endothelium of ex vivo corneas and in cultured cells by immunocytochemistry. Western blot analysis verified PTP1B protein expression in HCEC and then compared the relative expression of EGFR and PTP1B in HCEC from young (<3 years old) and older donors (>60 years old). The effect of inhibiting the activity of PTP1B on S-phase entry was tested by comparing time-dependent BrdU incorporation in subconfluent HCEC incubated in the presence or absence of the PTP1B inhibitor, CinnGEL 2Me, before EGF stimulation. Results: PTP1B was localized in a punctate pattern mainly within the cytoplasm of HCEC in ex vivo corneas and cultured cells. Western blots revealed the presence of three PTP1B-positive bands in HCEC and the control. Further western blot analysis showed no significant age-related difference in expression of EGFR (p=0.444>0.05); however, PTP1B expression was significantly higher in HCEC from older donors (p=0.024<0.05). Pre-incubation of HCEC with the PTP1B inhibitor significantly increased (p=0.019<0.05) the number of BrdU positive cells by 48 h after EGF stimulation. Conclusions: Both immunolocalization and western blot studies confirmed that PTP1B is expressed in HCEC. Staining patterns strongly suggest that at least a subset of PTP1B is localized to the cytoplasm and most likely to the endoplasmic reticulum, the known site of EGFR/PTP1B interaction following EGF stimulation. PTP1B expression, but not EGFR expression, was elevated in HCEC from older donors, suggesting that the reduced proliferative activity of these cells in response to EGF is due, at least in part, to increased PTP1B activity. The fact that inhibition of PTP1B increased the relative number of cells entering S-phase strongly suggests that PTP1B helps negatively regulate EGF-stimulated cell cycle entry in HCEC. These results also suggest that it may be possible to increase the proliferative activity of HCEC, particularly in cells from older donors, by inhibiting the activity of this important protein tyrosine phosphatase.
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    Transcription Factor IRF8 Directs a Silencing Programme for TH17 Cell Differentiation
    (Nature Publishing Group, 2011) Ouyang, Xinshou; Zhang, Ruihua; Yang, Jianjun; Li, Qingshan; Qin, Lihui; Liu, Jianguo; Ning, Huan; Shin, Min Sun; Gupta, Monica; Qi, Chen-Feng; Lira, Sergio A.; Morse, Herbert C.; Ozato, Keiko; Mayer, Lloyd; Xiong, Huabao; Zhu, Cheng; He, John Cijiang
    T\(_H\)17 cells are recognized as a unique subset of T helper cells that have critical roles in the pathogenesis of autoimmunity and tissue inflammation. Although RORγt is necessary for the generation of T\(_H\)17 cells, the molecular mechanisms underlying the functional diversity of T\(_H\)17 cells are not fully understood. Here we show that a member of interferon regulatory factor (IRF) family of transcription factors, IRF8, has a critical role in silencing T\(_H\)17-cell differentiation. Mice with a conventional knockout, as well as a T cell-specific deletion, of the Irf8 gene exhibited more efficient T\(_H\)17 cells. Indeed, studies of an experimental model of colitis showed that IRF8 deficiency resulted in more severe inflammation with an enhanced T\(_H\)17 phenotype. IRF8 was induced steadily and inhibited T\(_H\)17-cell differentiation during T\(_H\)17 lineage commitment at least in part through its physical interaction with RORγt. These findings define IRF8 as a novel intrinsic transcriptional inhibitor of T\(_H\)17-cell differentiation.