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Articles by L Yin
Total Records ( 4 ) for L Yin
  D Raina , R Ahmad , M. D Joshi , L Yin , Z Wu , T Kawano , B Vasir , D Avigan , S Kharbanda and D. Kufe

The mucin 1 (MUC1) oncoprotein is aberrantly overexpressed by ~90% of human breast cancers. However, there are no effective agents that directly inhibit MUC1 and induce death of breast cancer cells. We have synthesized a MUC1 inhibitor (called GO-201) that binds to the MUC1 cytoplasmic domain and blocks the formation of MUC1 oligomers in cells. GO-201, and not an altered version, attenuates targeting of MUC1 to the nucleus of human breast cancer cells, disrupts redox balance, and activates the DNA damage response. GO-201 also arrests growth and induces necrotic death. By contrast, the MUC1 inhibitor has no effect on cells null for MUC1 expression or nonmalignant mammary epithelial cells. Administration of GO-201 to nude mice bearing human breast tumor xenografts was associated with loss of tumorigenicity and extensive necrosis, which results in prolonged regression of tumor growth. These findings show that targeting the MUC1 oncoprotein is effective in inducing death of human breast cancer cells in vitro and in tumor models. [Cancer Res 2009;69(12):5133–41]

  R Bao , C. J Lai , H Qu , D Wang , L Yin , B Zifcak , R Atoyan , J Wang , M Samson , J Forrester , S DellaRocca , G. X Xu , X Tao , H. X Zhai , X Cai and C. Qian

Purpose: We designed and synthesized CUDC-305, an HSP90 inhibitor of the novel imidazopyridine class. Here, we report its unique pharmacologic properties and antitumor activities in a variety of tumor types.

Experimental Design: The potency of the compound was analyzed by fluorescence polarization competition binding assay. Its antiproliferative activities were assessed in 40 human cancer cell lines. Its pharmacologic properties and antitumor activities were evaluated in a variety of tumor xenograft models.

Results: CUDC-305 shows high affinity for HSP90/β (IC50, ~100 nmol/L) and HSP90 complex derived from cancer cells (IC50, 48.8 nmol/L). It displays potent antiproliferative activity against a broad range of cancer cell lines (mean IC50, 220 nmol/L). CUDC-305 exhibits high oral bioavailability (96.0%) and selective retention in tumor (half-life, 20.4 hours) compared with normal tissues. Furthermore, CUDC-305 can cross blood-brain barrier and reach therapeutic levels in brain tissue. CUDC-305 exhibits dose-dependent antitumor activity in an s.c. xenograft model of U87MG glioblastoma and significantly prolongs animal survival in U87MG orthotopic model. CUDC-305 also displays potent antitumor activity in animal models of erlotinib-resistant non–small cell lung cancer and induces tumor regression in animal models of MDA-MB-468 breast cancer and MV4-11 acute myelogenous leukemia. Correlating with its efficacy in these various tumor models, CUDC-305 robustly inhibits multiple signaling pathways, including PI3K/AKT and RAF/MEK/ERK, and induces apoptosis. In combination studies, CUDC-305 enhances the antitumor activity of standard-of-care agents in breast and colorectal tumor models.

Conclusion: CUDC-305 is a promising drug candidate for the treatment of a variety of cancers, including brain malignancies.

  N Wu , L Yin , E. A Hanniman , S Joshi and M. A. Lazar

Intracellular heme levels must be tightly regulated to maintain proper mitochondrial respiration while minimizing toxicity, but the homeostatic mechanisms are not well understood. Here we report a novel negative feedback mechanism whereby the nuclear heme receptor Rev-erb tightly controls the level of its own ligand. Heme binding to Rev-erb recruits the NCoR/histone deacetylase 3 (HDAC3) corepressor complex to repress the transcription of the coactivator PGC-1, a potent inducer of heme synthesis. Depletion of Rev-erb derepresses PGC-1, resulting in increased heme levels. Conversely, increased Rev-erb reduces intracellular heme, and impairs mitochondrial respiration in a heme-dependent manner. Consistent with this bioenergetic impairment, overexpression of Rev-erb dramatically inhibits cell growth due to a cell cycle arrest. Thus, Rev-erb modulates the synthesis of its own ligand in a negative feedback pathway that maintains heme levels and regulates cellular energy metabolism.

  Y Hu , B Tian , G Xu , L Yin , X Hua , J Lin and Y. Hua

The bacterium Deinococcus radiodurans is extremely resistant to the intense ionizing irradiation which causes extensive DNA double-strand breaks (DSBs). The deinococcal SbcCD complex (drSbcCD) is required for DSB repair. The drSbcC and drSbcD genes were cloned and overexpressed in Escherichia coli cells, respectively. The nearly homogeneous drSbcC and drSbcD proteins were purified and reconstituted to form a stable complex in vitro. The drSbcCD complex has an ATP-independent 3'->5' exonuclease activity to cleave both dsDNA and ssDNA substrates in the presence of either Mn2+ or Mg2+ ion. The drSbcCD complex also has an ATP-independent endonuclease activity. It can cleave the circular ssDNA, nick the supercoiled circular dsDNA, cleave the 3' flap DNA substrate at the site of the single-strand branch adjacent to duplex DNA, and cleave the hairpin DNA taking no account of the DNA end free or not. It is a kind of secondary structure-specific endonuclease. The drSbcCD complex still has a 3'->5' exonuclease activity when the DNA termini are blocked by the proteins. These results suggest that the drSbcCD complex takes part in the metabolism of DNA, and its nuclease activities may play important roles in DNA repair process.

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