A channel-associated protein PSD-95 has been shown to induce clustering of N-methyl D-aspartate (NMDA) receptors, interacting with the COOH terminus of the ⑀ subunit of the receptors. The effects of PSD-95 on the channel activity of the ⑀2/1 heteromeric NMDA receptor were examined by injection of PSD-95 cRNA into Xenopus oocytes expressing the NMDA receptors. Expression of PSD-95 decreased the sensitivity of the NMDA receptor channels to L-glutamate. Mutational studies showed that the interaction between the COOH terminus of the ⑀2 subunit of the NMDA receptor and the second PSD-95/Dlg/Z0-1 domain of PSD-95 is critical for the decrease in glutamate sensitivity. It is known that protein kinase C markedly potentiates the channel activity of the NMDA receptor expressed in oocytes. PSD-95 inhibited the protein kinase C-mediated potentiation of the channels. Thus, we demonstrated that PSD-95 functionally modulates the channel activity of the ⑀2/1 NMDA receptor. PSD-95 makes signal transmission more efficient by clustering the channels at postsynaptic sites. In addition to this, our results suggest that PSD-95 plays a protective role against neuronal excitotoxicity by decreasing the glutamate sensitivity of the channels and by inhibiting the protein kinase C-mediated potentiation of the channels.The NMDA 1 receptor is a subclass of ionotropic glutamate receptors in the mammalian brain. The NMDA receptors exhibit several channel properties distinct from other non-NMDA glutamate receptors, including a high Ca 2ϩ /Na ϩ permeability ratio, a voltage-dependent Mg 2ϩ block, and a requirement for glycine as co-agonist (1-4). The receptors are modulated by phosphorylation catalyzed by protein kinase C (5, 6) and by tyrosine kinases (7,8). In brain, functional NMDA receptors are thought to exist as heteromultimers of the 1 subunit (NR1) with ⑀ subunits (NR2 subunits). Different combinations of these subunits exhibit distinct channel properties and characteristic regional and developmental expression in vivo (9 -11). Disruption of the 1 gene is lethal in mice (12), whereas that of the ⑀1 and ⑀2 genes results in reduced channel activity and reduced LTP in the hippocampus (13,14). A number of evidences indicate that the activation of NMDA receptors is essential for induction of LTP, which underlies the formation and storage of some forms of memories (15).NR2 subunits (⑀ subunits) have been shown to interact specifically with PSD-95 (postsynaptic density-95) (16 -19). The latter protein is a member of the channel-associated proteins (PSD-95 family), including SAP97 (synaptic associated protein 97)/hdlg (20, 21), chapsin-110/PSD-93 (22, 23), and SAP102 (24). This family of proteins is characterized by the presence of three domains with a length of ϳ90 amino acids (PDZ domain) in the NH 2 -terminal region, followed by SH3 and guanylate kinase-like domains. PSD-95 was shown to interact with the COOH-terminal E(T/S)XV sequence motif of NMDA receptor ⑀ subunits (18, 19) and of K ϩ channels through the NH 2 -terminal PDZ domains (25,26)...

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Although lobular endocervical glandular hyperplasia (LEGH) was originally described as a distinct hyperplastic glandular lesion of the uterine cervix, recent studies have raised a question that LEGH may be a cancerous precursor of minimal deviation adenocarcinoma (MDA) and other mucinous adenocarcinomas (MACs) of the uterine cervix. In the present study, we studied LEGH, MDA, and MAC by using molecular-genetic and immunohistochemical methods for chromosomal imbalance, microsatellite instability, human papillomavirus (HPV) infection, and gastric pyloric-type mucin secretion to clarify their relationship. Comparative genomic hybridization revealed recurrent chromosomal imbalances, that is, gains of chromosome 3q and a loss of 1p, which were common to MDA and MAC, in 3 of 14 LEGHs analyzed (21%). LEGHs with chromosomal imbalances showed a degree of cellular atypia in the hyperplastic glandular epithelium. Dual-color fluorescence in situ hybridization confirmed a gain of chromosome 3 fragment in these cervical glandular lesions. HPV in situ hybridization revealed that high-risk HPV (types 16 and 18) was positive in over 80% of MACs, but negative in all LEGHs and MDAs examined. Microsatellite instability was rarely detected in these cervical glandular lesions. Our present study results demonstrated a molecular-genetic link between LEGH and cervical mucinous glandular malignancies including MDA and MAC, and are thought to support the hypothesis that a proportion of LEGHs are cancerous precursors of MDA and/or MAC.

Objective: To search for a biological marker to distinguish low-risk from high-risk bladder cancer indicating disease progression. Methods: The whole genome-wide copy numbers were screened in 18 patients with bladder cancer using array comparative genomic hybridization (CGH) consisting of 4,030 bacterial artificial chromosome clones. Results: Gain of 5p15.33, including TPPP (tubulin polymerization-promoting protein)and ZDHHC11 (zinc finger DHHC domain-containing protein 11) genes, was detected in 5 of 9 (55.6%) high-grade bladder cancers and no (0%; n = 9) low-grade bladder cancer. To confirm the preliminary data, 5p15.33 gain was studied by fluorescence in situhybridization (FISH) in 100 patients, and the results were compared with biological characteristics. In FISH analysis, gain of 5p15.33 was significantly correlated with higher histological grade (p < 0.0001) and advanced pathological stage (p = 0.0284). Tumors with a gain of 5p15.33 had a significantly higher progression-free survival rate than those without (p = 0.0006, log-rank test). Multivariate analysis revealed that gain of 5p15.33 was a predictor for disease progression in bladder cancer (hazard ratio: 1.887, 95% confidence interval: 1.215–2.968, p = 0.0050). Conclusion: These data suggest that gain of 5p15.33 (TPPP and ZDHHC11) may become a potential biomarker identifying high-risk patients with disease progression in bladder cancer.

Background: With tumor progression, genomic aberrations accumulate in cancer cells