Cells contain a large pool of nonpumping Na/K-ATPase that participates in signal transduction. Here, we show that the expression of ␣1 Na/K-ATPase is significantly reduced in human prostate carcinoma as well as in several human cancer cell lines. This down-regulation impairs the ability of Na/KATPase to regulate Src-related signaling processes. A supplement of pNaKtide, a peptide derived from ␣1 Na/K-ATPase, reduces the activities of Src and Src effectors. Consequently, these treatments stimulate apoptosis and inhibit growth in cultures of human cancer cells. Moreover, administration of pNaKtide inhibits angiogenesis and growth of tumor xenograft. Thus, the new findings demonstrate the in vivo effectiveness of pNaKtide and suggest that the defect in Na/K-ATPase-mediated signal transduction may be targeted for developing new anticancer therapeutics. Na/K-ATPase was originally discovered as an ion pump that is essential for cell vitality and provides a means for epithelium to secrete and/or absorb solutes and nutrients (1, 2). Recent studies have revealed that in addition to pumping ions across the cell membrane, Na/K-ATPase, specifically the ␣1 isoform, conducts many nonpumping functions, including scaffolding and signal transduction. As a signaling protein, it is involved in the formation of membrane structures such as tight junction and caveolae (3, 4). Moreover, a large fraction of cellular Na/KATPase is involved in tethering and regulating multiple protein and lipid kinases as well as membrane receptors (e.g. Src, human epidermal growth factor receptor, and PI3K) in a cellspecific manner (5, 6). Recently, the ␣1 Na/K-ATPase-Src receptor complex has been identified as one of the central components of ␣1 Na/K-ATPase-mediated signaling transduction (7). In this receptor complex, the Src SH2 domain binds to the second cytosolic domain, whereas the Src kinase domain interacts with the nucleotide binding (N) domain 4 of the ␣1 subunit. The latter interaction keeps Src in an inactive state (7). It is important to note that normal epithelial cells express approximately one million ␣1 Na/K-ATPase molecules (roughly five times the amount of Src). Thus, ␣1 Na/K-ATPase could provide at least two ways of regulating cellular Src activity. First, it could bind and keep Src in an inactive state. Consistently, when knock-out of one copy of the ␣1 gene caused a 20 -30% reduction in cellular ␣1 Na/K-ATPase, it produced a Ͼ2-fold increase in Src and ERK activities in tissues of ␣1 ϩ/Ϫ mice (8). Second, formation of the Na/K-ATPase-Src complex provides a functional receptor for endogenous cardiotonic steroids such as ouabain to regulate cellular signaling via Src and Src effectors (7, 9). Thus, changes in cellular ␣1 Na/K-ATPase would have a significant effect on cellular signaling events induced by either cardiotonic steroids or other growth factors through Src-related pathways.Based on the fact that the N domain of the ␣1 subunit binds and inhibits Src, we have recently made pNaKtide from the N domain of the human ␣1 subunit of...

Our study indicated that simultaneous delivery of two antifibrotic genes could confer synergistic effect on hepatic fibrosis.

We have screened a chemical library and identified several novel structures of Na/K-ATPase inhibitors.

Scavenger receptor class B type I (SR-BI) is the high-affinity high-density lipoprotein (HDL) receptor, and CLA-1 is the human homologue of the murine SR-BI. CLA-1/SR-BI receptor has been suggested as a new preventative and/or therapeutic target for atherosclerosis due to its pivotal role in overall HDL cholesterol (HDL-C) metabolism and its antiatherogenic activity in vivo. To search for active compounds that can increase CLA-1 transcription, a novel cell-based assay was developed for application in high-throughput screening (HTS). Human hepatoma HepG2 cells were transfected with a CLA-1-promoter-luciferase reporter gene construct, and the stable transfected cell line was selected and named CLAp-LUC HepG2. With rosiglitazone as a positive control, this stable cell line was used to establish a specific CLA-1 gene expression assay in a 96-well microplate format. The evaluating parameter Z´ value of 0.64 showed that this cell-based HTS assay was robust and reliable. Screening of 6000 microbial secondary metabolite crude extracts identified 8 positive strains. Between 2 identified CLA-1 up-regulators produced by actinomycete strain 04-4776, 4776B may stimulate not only the expression of CLA-1 on the transcriptional and translational levels but also the activity of CLA-1 to uptake the HDL-C in HepG2 cells. The active compounds originated from this HTS assay may be developed to drug candidates or lead compounds for new antiatherosclerosis agents. (Journal of Biomolecular Screening 2007:211-219)

The pulse radiation detectors are sorely needed in the fields of nuclear reaction monitoring, material analysis, astronomy study, spacecraft navigation, and space communication. In this work, we demonstrate a nanosecond X-ray detector based on ZnO single crystal semiconductor, which emerges as a promising compound-semiconductor radiation detection material for its high radiation tolerance and advanced large-size bulk crystal growth technique. The resistivity of the ZnO single crystal is as high as 1013 Ω cm due to the compensation of the donor defects (VO) and acceptor defects (VZn and Oi) after high temperature annealing in oxygen. The photoconductive X-ray detector was fabricated using the high resistivity ZnO single crystal. The rise time and fall time of the detector to a 10 ps pulse electron beam are 0.8 ns and 3.3 ns, respectively, indicating great potential for ultrafast X-ray detection applications.