A ferroelectric transition occurring simultaneously with helical spin order has been found in both the polycrystalline and single crystal samples of LiCuVO 4 . The system has Cu 2+ spins (s=1/2) of the CuO 2 chains formed of edge-sharing CuO 4 squares. Possibly due to the frustrated nature caused by the competition between the nearest-neighbor and next-nearest-neighbor exchange interactions, Cu spins exhibit, as has been already reported, the helical magnetic order with the incommensurate modulation vector Q along the chain direction and with the helical axis e 3 perpendicular to the CuO 4 squares. The electric polarization P can be understood by the recently predicted relation P ∝ Q×e 3 . The transition temperature has been found to be gradually suppressed by the applied magnetic field.

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We have previously demonstrated that phosphorylation of neuronal nitric-oxide synthase (nNOS) at Ser(847) by Ca(2+)/calmodulin-dependent protein kinases (CaM kinases) attenuates the catalytic activity of the enzyme in vitro (Hayashi Y., Nishio M., Naito Y., Yokokura H., Nimura Y., Hidaka H., and Watanabe Y. (1999) J. Biol. Chem. 274, 20597-20602). In the present study we determined that CaM kinase IIalpha (CaM-K IIalpha) can directly phosphorylate nNOS on Ser(847), leading to a reduction of nNOS activity in cells. The phosphorylation abilities of purified CaM kinase Ialpha (CaM-K Ialpha), CaM-K IIalpha, and CaM-kinase IV (CaM-K IV) on Ser(847) were analyzed using the synthetic peptide nNOS-(836-859) (Glu-Glu-Arg-Lys-Ser-Tyr-Lys-Val-Arg-Phe-Asn-Ser-Val-Ser-Ser-Tyr-Ser- Asp-Ser-Arg-Lys-Ser-Ser-Gly) from nNOS as substrate. The relative V(max)/K(m) ratios of CaM kinases for nNOS-(836-859) were found to be as follows: CaM-K IIalpha, 100; CaM-K Ialpha, 54.5; CaM-K IV, 9.1. Co-transfection of constitutively active CaM-K IIalpha1-274 but not inactive CaM-K IIalpha1-274, generated by mutation of Lys(42) to Ala, with nNOS into NG108-15 cells, resulted in increased Ser(847) phosphorylation in the presence of okadaic acid, an inhibitor of protein phosphatase (PP)1 and PP2A, with a concomitant inhibition of NOS enzyme activity. In addition, this latter decrease could be reversed by treatment with exogenous PP2A. Cells expressing mutant nNOS (S847A) proved resistant to phosphorylation and a decrease of NOS activity. Thus, our results indicate that Ca(2+) triggers cross-talk signal transduction between CaM kinase and NO and CaM-K IIalpha phosphorylating nNOS on Ser(847), which in turn decreases the gaseous second messenger NO in neuronal cells.

Neutron scattering studies and measurements of the dielectric susceptibility ε and ferroelectric polarization P have been carried out in various magnetic fields H for single-crystal samples of the multiferroic system LiVCuO 4 with quasi one-dimensional spin 1/2 Cu 2+ chains formed of edge-sharing CuO 4 square planes, and the relationship between the magnetic structure and ferroelectricity has been studied. The ferroelectric polarization is significantly suppressed by the magnetic field H above 2 T applied along a and b axes. The helical magnetic structure with the helical axis parallel to c has been confirmed in H=0, and for H//a, the spin flop transition takes place at H=2 T with increasing H, where the helical axis changes to the direction parallel to H. The ferroelectric polarization along a at H=0 is found to be proportional to the neutron magnetic scattering intensity, indicating that the magnetic order is closely related to the appearance of the ferroelectricity. The relationship between the magnetic structure and ferroelectricity of LiVCuO 4 is discussed by considering the existing theories. dependence of the magnetic susceptibility, the broad peak attributed to the growth of the short-range spin correlation, typical for low-dimensional antiferromagnets, is observed at ~26 K and the sharp anomaly is observed at the transition temperature T N =2.4 K, which corresponds to the 3D long-range magnetic order. For this system, the exchange interaction between the nearest-neighbor Cu 2+ ions, J 1 is rather weak (Cu-O-Cu angle is ~95°), or even weaker than the next-nearest-neighbor interaction J 2 , suggesting that effects of the magnetic frustration are significant in its magnetic properties. Enderle et al. reported that J 1~-12 K (ferromagnetic) and J 2~4 1 K (antiferromagnetic) by the studies of magnetic excitation using inelastic neutron scattering. 8) Due to the magnetic frustration, the magnetic structure below T N is expected not to be trivial. Actually, the magnetic structure of LiVCuO 4 reported by Gibson et al. 9) is helical with the moments in the ab-plane (in the CuO 4 square planes) and with the incommensurate modulation vector along b. Based on the 7Li-NMR spectra, the magnetic structure in the applied magnetic field was also discussed.10) The authors' group reported a clear anomaly at T N in the T-dependence of the dielectric susceptibility ε for the electric field E//a, indicating that the ferroelectric transition takes place simultaneously with the magnetic transition. 6)In the present work, neutron scattering and measurements of dielectric susceptibility ε and ferroelectric polarization P have been carried out on single-crystal samples of LiVCuO 4 in the various magnetic fields. Based on results of these studies, the relationship between magnetic structure and ferroelectricity for LiVCuO 4 is discussed, in relation to the theoretical models on the occurrence of the multiferroic state. 11-16)Single-crystal samples of LiVCuO 4 used in the measurements of ε and P were grown by a flux method, as re...

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Myristoylated alanine-rich C kinase substrate (MARCKS) is considered to participate in formation of F-actin-based lamellipodia, which represents the first stage of neurite formation. However, the mechanism of how MARCKS is involved in lamellipodia formation is not precisely unknown. Using SH-SY5Y cells, we demonstrated here that MARCKS was translocated from cytosol to detergent-resistant membrane microdomains, known as lipid rafts, within 30 min after insulin-like growth factor-I (IGF-I) stimulation, which was accompanied by MARCKS dephosphorylation, beta-actin accumulation in lipid rafts, and lamellipodia formation. The protein kinase C inhibitor, Ro-31-8220, and Rho-kinase inhibitors, HA1077 and Y27632, themselves decreased basal phosphorylation levels of MARCKS and coincidently elicited translocation of MARCKS to lipid rafts. On the other hand, the phosphoinositide 3-kinase inhibitor, LY294002, abolished IGF-I-induced dephosphorylation, translocation of MARCKS to lipid rafts, and lamellipodia formation. Treatment of cells with neomycin, a PIP2-masking reagent, attenuated the translocation of MARCKS to lipid rafts and the lamellipodia formation induced by IGF-I, although dephosphorylation of MARCKS was not affected. Immunocytochemical and immunoprecipitation analysis indicated that IGF-I stimulation induced the translocation of MARCKS to lipid rafts in the edge of lamellipodia and formation of the complex with PIP2. Moreover, we demonstrated that knockdown of endogenous MARCKS resulted in significant attenuation of IGF-I-induced beta-actin accumulation in the lipid rafts and lamellipodia formation. These results suggest a novel role for MARCKS in lamellipodia formation induced by IGF-I via the translocation of MARCKS, association with PIP2, and accumulation of beta-actin in the membrane microdomains.

ObjectiveTo evaluate the efficacy of docetaxel and androgen receptor axis-targeted (ARAT) agents in patients with castrationresistant prostate cancer (CRPC) with intraductal carcinoma of the prostate (IDC-P) using a propensity score-matched analysis. ConclusionAdministration of ARAT as the first-line treatment for CRPC may prolong OS more than that of docetaxel, especially in patients with IDC-P.

We earlier confirmed that there are isoforms of Ca2+/calmodulin (CaM)-dependent protein kinase I (CaM kinase I) (CaM kinase Ibeta1 and Igamma) beside CaM kinase Ialpha by cDNA cloning (Yokokura, H., Terada, O., Naito, Y., and Hidaka, H. (1997) Biochim. Biophys. Acta 1338, 8-12). Here, we demonstrate the existence of an isoform-specific activation mechanism of CaM kinase I and alternative splicing specifically regulating CaM kinase I (CaM kinase Ibeta2) in the central nervous system. To cast light on isoform structure-enzyme activity relationships, CaM kinase Ibeta1, Ibeta2, and Ialpha were expressed separately using a baculovirus/Sf9 cell expression system. The novel CaM kinase Ibeta2 isoform demonstrated similar catalytic activity to those of CaM kinase Ibeta1 and Ialpha. Interestingly, CaM kinase Ibeta1 and Ibeta2 both can activate CaM kinase Ialpha activity via phosphorylation at Thr177. Reverse transcribed-polymerase chain reaction analysis showed that CaM kinase Ibeta2 is dominant in the cerebrum and cerebellum, whereas CaM kinase Ibeta1 is present in peripheral tissues such as liver, heart, lung, kidney, spleen, and testis. CaM kinase Ibeta2 was also detected with an anti-CaM kinase Ibeta2 antibody in PC12 cells. The results indicate that alternative splicing is a means for tissue-specific expression of CaM kinase Ibeta. Thus the Thr177 residue of CaM kinase Ialpha is phosphorylated by not only CaM kinase kinase but also CaM kinase Ibeta for activation of the enzyme.