Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Leucine-rich repeat receptor-like kinases (LRR RLKs) comprise the largest group within the plant receptor-like kinase (RLK) superfamily, and the Arabidopsis genome alone contains over 200 LRR RLK genes. Although there is clear evidence for diverse roles played by individual LRR RLK genes in Arabidopsis growth and development, the evolutionary mechanism for this functional diversification is currently unclear. In this study, we focused on the LRRII RLK subfamily to investigate the molecular mechanisms that might have led to the functional differentiation of Arabidopsis LRR RLK genes. Phylogenetic analysis of 14 genes in this subfamily revealed three well-supported groups (I, II, and III). RT-PCR analysis did not find many qualitative differences in expression among these 14 genes in various Arabidopsis tissues, suggesting that evolution of regulatory sequences did not play a major role in their functional divergence. We analyzed substitution patterns in the predicted ligand-binding regions of these genes to examine if positive selection has acted to produce novel ligand-binding specificities, using the nonsynonymous/synonymous rate ratio (d (N)/d (S)) as an indicator of selective pressure. Estimates of d (N)/d (S) ratios from multiple methods indicate that nonsynonymous substitutions accumulated during divergence of the three lineages. Positive selection is likely to have occurred along the lineages ancestral to groups II and III. We suggest that positive selection on the ligand-binding sites of LRRII RLKs promoted diversification of ligand-binding specificities and thus contributed to the functional differentiation of Arabidopsis LRRII RLK genes during evolution.
J Mol Evol 2006 Nov
PMID:Domain-specific positive selection contributes to the evolution of Arabidopsis leucine-rich repeat receptor-like kinase (LRR RLK) genes. 1703 60

Transforming growth factor beta superfamily ligands regulate pituitary FSH production and secretion. The best-described examples are the activins and inhibins, which respectively stimulate and hinder Fshb subunit transcription in gonadotrope cells. More recently, members of the bone morphogenetic protein (BMP) sub-family were shown to regulate FSH production in a manner analogous to the activins. Here, we used the murine gonadotrope cell line, LbetaT2, to investigate mechanisms through which BMP2 regulates the Fshb gene. Although expressed at low levels in LbetaT2 cells, Bmp2 mRNA was readily detected in adult murine pituitary gland. Recombinant BMP2 stimulated Fshb promoter-reporter activity, although its effects were weaker than those of equimolar activin A or B. BMP4 stimulated transcription comparably with BMP2, but BMPs 6 and 7 were about tenfold less potent. Remarkably, BMP2 and activin A synergistically upregulated Fshb transcription and endogenous Fshb mRNA levels in LbetaT2 cells. Although functionally cooperative, the two ligands appeared to use distinct intracellular mechanisms to mediate their responses because neither ligand altered the timing or magnitude of the other's effects. Receptor overexpression analyses suggested that BMP2 may preferentially signal through complexes of the type II receptor, BMPR2, and the type I receptor, activin receptor like kinase (ALK2; Acvr1), to stimulate Fshb transcription. BMP2 rapidly activated the Smad1/5/8 intracellular signaling cascade and Smad8 overexpression potentiated BMP2's effects. In summary, BMPs regulate Fshb transcription in LbetaT2 cells and can amplify the already robust effects of the activins through a distinct signaling mechanism. Because BMP2 is expressed in the adult mouse pituitary, it may act as critical paracrine co-regulator of FSH synthesis by gonadotropes.
J Mol Endocrinol 2007 Feb
PMID:Bone morphogenetic protein 2 and activin A synergistically stimulate follicle-stimulating hormone beta subunit transcription. 1729 49

Perception of general elicitors by plant cells initiates signal transduction cascades that are regulated by protein phosphorylation. The earliest signaling events occur within minutes and include ion fluxes across the plasma membrane, activation of MAPKs, and the formation of reactive oxygen species. The phosphorylation events that regulate these signaling cascades are largely unknown. Here we present a mass spectrometry-based quantitative phosphoproteomics approach that identified differentially phosphorylated sites in signaling and response proteins from Arabidopsis cells treated with either flg22 or xylanase. Our approach was sensitive enough to quantitate phosphorylation on low abundance signaling proteins such as calcium-dependent protein kinases and receptor-like kinase family members. With this approach we identified one or more differentially phosphorylated sites in 76 membrane-associated proteins including a number of defense-related proteins. Our data on phosphorylation indicate a high degree of complexity at the level of post-translational modification as exemplified by the complex modification patterns of respiratory burst oxidase protein D. Furthermore the data also suggest that protein translocation and vesicle traffic are important aspects of early signaling and defense in response to general elicitors. Our study presents the largest quantitative Arabidopsis phosphoproteomics data set to date and provides a new resource that can be used to gain novel insight into plant defense signal transduction and early defense response.
Mol Cell Proteomics 2007 Jul
PMID:Quantitative phosphoproteomics of early elicitor signaling in Arabidopsis. 1731 60

PCD (programmed cell death) is important mechanism for development, homeostasis and disease. To analyze the gene expression pattern in brain cells undergoing PCD in response to serum deprivation, we analyzed the cDNA microarray consisting of 2,300 genes and 7 housekeeping genes of cortical cells derived from mouse embryonic brain. Cortical cells were induced apoptosis by serum deprivation for 8 hours. We identified 69 up-regulated genes and 21 down-regulated genes in apoptotic cells. Based on the cDNA microarray data four genes were selected and analyzed by RT-PCR and northern blotting. To characterize the role of UNC-51-like kinase (ULK2) gene in PCD, we investigated cell death effect by ULK2. And we examined expression of several genes that related with PCD. Especially GAPDH was increased by ULK2. Theses findings indicated that ULK2 is involved in apoptosis through p53 pathway.
J Biochem Mol Biol 2007 Mar 31
PMID:The gene expression profiling in murine cortical cells undergoing programmed cell death (PCD) induced by serum deprivation. 1739 79

The GSK3/Shaggy family of serine/threonine protein kinases is involved in a series of biological processes in animals, plants and yeast [Charrier et al. (2002) Plant Physiol 130:577-590; Jope and Johnson (2004) Trends Biochem Sci 29:95-102; Li and Nam (2002) Science 295:1299-1301; Piao et al. (2001) Plant J 27:305-314]. In Arabidopsis thaliana, out of the 10 members of the GSK3/Shaggy-like gene family (AtSKs), a biological function has been assigned to only 1 member (AtSK2-1) by mutation. In the present work, a study was undertaken to elucidate the function of AtSK3-2. We have generated mutated versions of the A. thaliana Shaggy-like kinase 3-2 (AtSK3-2), in which Lys(167) and Arg(178), respectively homologues to Lys(85) and Arg(96) of the mammal GSK3beta, were modified into Ala by site-directed mutagenesis. In vitro kinase activity assays of the mutated recombinant protein AtSK3-2-R178A showed that the "primed activity" of the mutated kinase was reduced by 90% while the "non-primed" activity was only 20% reduced compared to the wild-type protein kinase. However, the mutant protein AtSK3-2-K167A showed no activity. Arabidopsis transgenic lines over-expressing AtSK3-2-R178A displayed smaller floral organs, namely pedicels, sepals and petals. Conversely, over-expression of both the wild-type AtSK3-2 protein and the AtSK3-2-K167A mutated version, displayed no altered morphogenesis. Scanning electron microscopic analyses of the AtSK3-2-R178A transgenic plants clearly showed a reduced cell size in flower organs, in which quantitative RT-PCR expression analyses of cell wall expansion enzymes showed reduced transcript levels of three xyloglucan endotransglycosylases (XET), namely XTH22 (TCH4), XTH23 (XTR6) and XTH30 (XTR4). Our data show that AtSK3-2 plays an important role in the control of cell elongation in flower development.
Plant Mol Biol 2007 May
PMID:The Arabidopsis thaliana GSK3/Shaggy like kinase AtSK3-2 modulates floral cell expansion. 1742 40

Hydroxyurea (HU) is a DNA replication inhibitor that negatively affects both the elongation and initiation phases of replication and triggers the "intra-S phase checkpoint." Previous work with budding yeast has shown that, during a short exposure to HU, MEC1/RAD53 prevent initiation at some late S phase origins. In this study, we have performed microarray experiments to follow the fate of all origins over an extended exposure to HU. We show that the genome-wide progression of DNA synthesis, including origin activation, follows the same pattern in the presence of HU as in its absence, although the time frames are very different. We find no evidence for a specific effect that excludes initiation from late origins. Rather, HU causes S phase to proceed in slow motion; all temporal classes of origins are affected, but the order in which they become active is maintained. We propose a revised model for the checkpoint response to HU that accounts for the continued but slowed pace of the temporal program of origin activation.
Mol Cell Biol 2007 Sep
PMID:Replication in hydroxyurea: it's a matter of time. 1763 20

Genistein has been shown to inhibit human prostate cancer (PCa) cell motility. Endoglin has been identified as an important suppressor of PCa cell motility, and its expression is lost during PCa progression. It is therefore important to determine whether endoglin loss affects genistein's efficacy and, if so, by what mechanism. In the current study, genistein was shown to induce reversion of endoglin-deficient cells to a low motility, endoglin-replete phenotype. Because endoglin suppresses PCa cell motility in an activin-like kinase receptor-2 (ALK2)- and Smad1-dependent manner, we sought to determine whether genistein was activating the ALK2-Smad1 pathway. Although treatment with genistein or overexpression of Smad1 or ALK2 all increased Smad1-responsive promoter activity and decreased cell motility, genistein's efficacy was abrogated by either Smad1 or ALK2 knockdown. Furthermore, transfection of cells with a kinase dead mutant of ALK2 abrogated genistein's efficacy. Together, these findings demonstrate that genistein therapeutically induces reversion to a low-motility phenotype in aggressive endoglin-deficient PCa cells. It does so by activating ALK2-Smad1 endoglin-associated signaling. These findings support the notion that individuals with low endoglin-expressing PCa will benefit from genistein treatment.
Mol Pharmacol 2008 Jan
PMID:Genistein induces phenotypic reversion of endoglin deficiency in human prostate cancer cells. 1795 57

Symbiotic nitrogen fixation with nitrogen-fixing bacteria in the root nodules is a distinctly beneficial metabolic process in legume plants. Legumes control the nodule number and nodulation zone through a systemic negative regulatory system between shoot and root. Mutation in the soybean NTS gene encoding GmNARK, a CLAVATA1-like serine/threonine receptor-like kinase, causes excessive nodule development called hypernodulation. To examine the effect of nts mutation on the gene expression profile in the leaves, suppression subtractive hybridization was performed with the trifoliate leaves of nts mutant 'SS2-2' and the wild-type (WT) parent Sinpaldalkong2, and 75 EST clones that were highly expressed in the leaves of the SS2-2 mutant were identified. Interestingly, the expression of jasmonate (JA)-responsive genes such as vspA, vspB, and Lox2 were upregulated, whereas that of a salicylate-responsive gene PR1a was suppressed in the SS2-2 mutant. In addition, the level of JA was about two-fold higher in the leaves of the SS2-2 mutant than in those of the WT under natural growth conditions. Moreover, the JA-responsive gene expression persists in the leaves of SS2-2 mutant without rhizobia infection in the roots. Taken together, our results suggest that the nts mutation increases JA synthesis in mature leaves and consequently leads to constitutive expression of JA-responsive genes which is irrelevant to hypernodulation in the root.
Mol Cells 2007 Oct 31
PMID:The Hypernodulating nts mutation induces jasmonate synthetic pathway in soybean leaves. 1797 70

We have previously shown that interleukin (IL)-1beta, transforming growth factor (TGF)-beta1, or bradykinin (BK) impair cAMP generation in response to prostacyclin analogs in human pulmonary artery smooth muscle (PASM), suggesting that inflammation can impair the effects of prostacyclin analogs on PASM in pulmonary hypertension. Here we explored the biochemical mechanisms involved. We found that IL-1beta, BK, and TGF-beta1 reduced adenylyl cyclase isoform 1, 2, and 4 mRNA, increased Galphai protein levels, and reduced prostacyclin receptor (IP receptor) mRNA expression. In contrast, Galphas protein levels were unchanged. Protein kinase A (PKA) (H-89, KT-2750, PKIm) and p38 mitogen-activated protein (MAP) kinase (SB-202190) inhibitors attenuated these effects, but protein kinase C (bisindolylmaleide) or phosphoinositol 3-kinase (LY-294002) inhibitors did not. Fluorescent kemptide assay and Western blotting confirmed that PKA and p38 MAP kinase were activated by IL-1beta, BK, and TGF-beta1. These studies suggest that IL-1beta, BK, and TGF-beta1 impair IP receptor-mediated cAMP accumulation by multiple effects on different components of the signaling pathway and that these effects are PKA and p38 MAP kinase dependent.
Am J Physiol Lung Cell Mol Physiol 2008 Mar
PMID:IL-1beta, BK, and TGF-beta1 attenuate PGI2-mediated cAMP formation in human pulmonary artery smooth muscle cells by multiple mechanisms involving p38 MAP kinase and PKA. 1815 42

The hepatocarcinogen aflatoxin B(1) (AFB(1)) is a potent recombinagen but weak mutagen in the yeast Saccharomyces cerevisiae. AFB(1) exposure induces DNA damage-inducible genes, such as RAD51 and those encoding ribonucleotide reductase (RNR), through a MEC1 (ATR homolog)-dependent pathway. Previous studies have indicated that MEC1 is required for both AFB(1)-associated recombination and mutation, and suggested that AFB(1)-DNA adducts are common substrates for recombination and mutagenesis. However, little is known about the downstream effectors of MEC1 required for genotoxic events associated with AFB(1) exposure. Here we show that AFB(1) exposure increases frequencies of RAD51-dependent unequal sister chromatid exchange (SCE) and activates Rad53 (CHK2). We found that MEC1, RAD53, and DUN1 are required for both AFB(1)-associated mutation and SCE. Deletion of SML1, which encodes an inhibitor of RNR, did not suppress the DUN1-dependent requirement for AFB(1)-associated genetic events, indicating that higher dNTP levels could not suppress the dun1 phenotype. We identified AFB(1)-DNA adducts and show that approximately the same number of adducts are obtained in both wild type and rad53 mutants. Since DUN1 is not required for UV-associated mutation and recombination, these studies define a distinct role for DUN1 in AFB(1)-associated mutagenesis and recombination. We speculate that AFB(1)-associated DNA adducts stall DNA replication, a consequence of which can either be mutation or recombination.
Mol Carcinog 2008 Aug
PMID:Stimulation of sister chromatid exchanges and mutation by aflatoxin B1-DNA adducts in Saccharomyces cerevisiae requires MEC1 (ATR), RAD53, and DUN1. 1822 55


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