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Lies Downstream (ly + downstream)
Selected AbstractsLocal activation of protein kinase A inhibits morphogenetic movements during Xenopus gastrulationDEVELOPMENTAL DYNAMICS, Issue 1 2003Byung-Ho Song Abstract cAMP-dependent protein kinase (PKA) has various biological roles in many organisms. However, little is known about its role in the developmental processes of vertebrates. In this study, we describe the functional analysis of PKA during gastrulation movements in Xenopus laevis. Overexpression of constitutively active PKA (cPKA) in the dorsal equatorial region of the embryo affects morphogenetic movement during gastrulation. We also show that intrinsic differences of PKA activities along the dorsoventral axis are set up and the level of PKA activity on the dorsal region is lower than that on the ventral region from late blastula to gastrula stages. In addition, PKA activation in animal explants inhibits activin-induced elongation. In cPKA-injected embryos, there were no changes in the expressions of markers involved in mesoderm specification, although the correct expression domains of these genes were altered. The effects of PKA activation can be restored by coexpression of PKI, a pseudosubstrate of PKA. We further analyzed the effects of PKA activation on the behavior of migratory gastrulating cells in vitro. Expression of cPKA in head mesoderm cells causes less polarized and/or randomized migration as demonstrated by a directional cell migration assay. Finally, we show that RhoA GTPase lies downstream of PKA, affecting activin-induced convergent extension movements. Taken together, these results suggest that overexpressed PKA can modulate a pathway responsible for morphogenetic movements during Xenopus gastrulation. Developmental Dynamics 227:91,103, 2003. © 2003 Wiley-Liss, Inc. [source] The quorum sensing regulator HapR downregulates the expression of the virulence gene transcription factor AphA in Vibrio cholerae by antagonizing Lrp- and VpsR-mediated activationMOLECULAR MICROBIOLOGY, Issue 4 2007Wei Lin Summary HapR is a quorum sensing-regulated transcription factor that represses the virulence cascade in Vibrio cholerae by binding to a specific site centred at ,71 in the aphA promoter, ultimately preventing activation of the tcpPH promoter on the Vibrio pathogenicity island. In an effort to elucidate the mechanism by which HapR represses aphA expression, we identified two transcriptional regulators, Lrp and VpsR, both of which activate the aphA promoter. Lrp, the leucine-responsive regulatory protein, binds to a region between ,136 and ,123 in the promoter to initiate aphA expression. VpsR, the response regulator that controls biofilm formation, binds to a region between ,123 and ,73 to activate aphA expression. HapR represses aphA expression by antagonizing the functions of both of these activators. The HapR binding site at ,71 lies downstream of the Lrp binding site and overlaps the VpsR binding site. HapR binding thus directly blocks access of VpsR to the promoter. A naturally occurring point mutation in the aphA promoter (G-77T), which has previously been shown to prevent HapR binding, also prevents VpsR binding. In the absence of HapR, either Lrp or VpsR is capable of achieving nearly full expression of the aphA promoter, but when present together their effects are to some degree additive. The aphA promoter is also negatively autoregulated and an AphA binding site is centred at ,20. The results here provide a model for the dual activation of the aphA promoter by Lrp and VpsR as well as its dual repression by HapR and AphA. [source] Characterization of the Staphylococcus aureus CidR regulon: elucidation of a novel role for acetoin metabolism in cell death and lysisMOLECULAR MICROBIOLOGY, Issue 2 2006Soo-Jin Yang Summary The Staphylococcus aureus cid and lrg operons encode a novel regulatory system that affects murein hydrolase activity, stationary-phase survival and antibiotic tolerance. Expression of the lrgAB operon is positively regulated by a two-component regulatory system encoded by the lytSR operon located immediately upstream to lrgAB. By comparison, the cidABC operon lies downstream from the cidR gene, encoding a protein homologous to the LysR-type family of transcriptional regulators. Transcription analysis of a cidR mutant revealed that CidR enhances cidABC expression in the presence of acetic acid generated by the metabolism of excess glucose. Microarray studies identified additional CidR-regulated operons including the IrgAB and alsSD encoding proteins involved in acetoin production. Surprisingly, Northern blot analyses revealed that cidABC and lrgAB transcription was uninducible in an alsSD mutant grown in the presence of excess glucose, suggesting that the CidR-mediated upregulation of cidABC and lrgAB transcription is dependent on the presence of intact alsSD genes. Zymographic and quantitative analyses of murein hydrolase activity also revealed that disruption of the alsSD genes results in significantly decreased extracellular murein hydrolase activity compared with that of the parental strain, UAMS-1. Furthermore, the alsSD mutant displayed decreased stationary-phase survival relative to UAMS-1, both in the presence and absence of glucose. The results of this study define the CidR regulon and demonstrate that the generation of acetoin is linked to the control of cell death and lysis in S. aureus. [source] VW Hyi: optical spectroscopy and Doppler tomographyMONTHLY NOTICES OF THE ROYAL ASTRONOMICAL SOCIETY, Issue 4 2006Amanda J. Smith ABSTRACT We present high-quality optical spectroscopy of the SU UMa-subtype dwarf nova, VW Hyi taken while the system was in quiescence. An S-wave is executed by the emission cores of the hydrogen Balmer lines and by the emission lines of He i, Ca ii, Fe ii and He ii. Using Doppler tomography, we show it originates in the accretion stream,disc impact region. The He ii emission is strongly phase-dependent, suggesting it originates exclusively within a hot cavity at the initial impact. We map the ionization structure of the stream,disc interaction region. One possible interpretation of this is that the Balmer hotspot lies downstream of the He ii hotspot in the outer accretion disc, with the He i and Ca ii hotspots at intermediate locations between the two. This suggests that Balmer emission is suppressed until material has cooled somewhat downstream of the impact site and is able to recombine. We favour a phase offset of 0.15 ± 0.04 between the photometric ephemeris and inferior conjunction of the mass donor. The white dwarf contributes significantly to the optical continuum, with broad Balmer absorption and narrow Mg ii ,4481 absorption clearly apparent. This latter feature yields the gravitational redshift: vgrav= 38 ± 21 km s ,1, so M1= 0.71+0.18,0.26 M,. This implies M2= 0.11 ± 0.03 M, and hence the donor is not a brown dwarf. A prominent Balmer jump is also observed. We note that the previously accepted system parameters for both VW Hyi and WX Hyi incorporate an algebraic error, and we provide a recalculated M1(q) plane for WX Hyi. [source] ZD6474 induces growth arrest and apoptosis of GIST-T1 cells, which is enhanced by concomitant use of sunitinibCANCER SCIENCE, Issue 12 2006Yang Yang ZD6474 (Zactima, AstraZeneca, Macclesfield, UK) is an orally available, small-molecule inhibitor of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor tyrosine kinases, with additional activity versus rearranged during transfection (RET). This study explored the effect of ZD6474 in gastrointestinal stromal tumor-T1 (GIST-T1) cells that possess a gain of function mutation in exon 11 of the c-KIT gene. ZD6474 induced growth arrest and apoptosis of GIST-T1 cells in association with blockade of c-Kit and its downstream effectors, including Akt and extracellular signal-regulated kinase (ERK). ZD6474 treatment also blocked the mammalian target of rapamycin (mTOR), which lies downstream of Akt and ERK. Interestingly, when ZD6474 was combined with sunitinib (SU11248; Sutent, Pfizer, Kalamazoo, MI, USA), a class III and V receptor tyrosine kinase inhibitor, the ZD6474-mediated growth inhibition was potentiated in association with further down-regulation of the mTOR targets p-p70S6K and p-4E-BP-1. The combination of ZD6474 and sunitinib should be investigated further. (Cancer Sci 2006; 97: 1404,1409) [source] | ||||||||||