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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Holoprosencephaly (HPE) is the most common developmental defect of the forebrain in humans. Several distinct human genes for holoprosencephaly have now been identified. They include Sonic hedgehog (SHH), ZIC2, and SIX3. Many additional genes involved in forebrain development are rapidly being cloned and characterized in model vertebrate organisms. These include Patched (Ptc), Smoothened (Smo), cubitus interuptus (ci)/Gli, wingless (wg/Wnt, decapentaplegic (dpp)/BMP, Hedgehog interacting protein (Hip), nodal, Smads, One-eyed pinhead (Oep), and TG-Interacting Factor (TGIF). However, further analysis is needed before their roles in HPE can be established. Here we present an overview of the presently known genes causing human holoprosencephaly and describe candidate genes involved in forebrain development identified in other systems. A model is discussed for how these genes may interact within and between several different signaling pathways to direct the formation of the forebrain.
Mol Genet Metab 1999 Oct
PMID:Molecular mechanisms of holoprosencephaly. 1052 64

We examined the nodal flow of well-characterized mouse mutants, inversus viscerum (iv) and inversion of embryonic turning (inv), and found that their laterality defects are always accompanied by an abnormality in nodal flow. In a randomized laterality mutant, iv, the nodal cilia were immotile and the nodal flow was absent. In a situs inversus mutant, inv, the nodal cilia was motile but could only produce very weak leftward nodal flow. These results consistently support our hypothesis that the nodal flow produces the gradient of putative morphogen and triggers the first L-R determination event.
Mol Cell 1999 Oct
PMID:Abnormal nodal flow precedes situs inversus in iv and inv mice. 1054 78

Cdc42p, a Rho family GTPase of the Ras superfamily, is a key regulator of cell polarity and morphogenesis in eukaryotes. Using 37 site-directed cdc42 mutants, we explored the functions and interactions of Cdc42p in the budding yeast Saccharomyces cerevisiae. Cytological and genetic analyses of these cdc42 mutants revealed novel and diverse phenotypes, showing that Cdc42p possesses at least two distinct essential functions and acts as a nodal point of cell polarity regulation in vivo. In addition, mapping the functional data for each cdc42 mutation onto a structural model of the protein revealed as functionally important a surface of Cdc42p that is distinct from the canonical protein-interacting domains (switch I, switch II, and the C terminus) identified previously in members of the Ras superfamily. This region overlaps with a region (alpha5-helix) recently predicted by structural models to be a specificity determinant for Cdc42p-protein interactions.
Mol Biol Cell 2000 Jan
PMID:Functions and functional domains of the GTPase Cdc42p. 1063 12

The left-right (L-R) asymmetric expression of lefty2 and nodal is controlled by a left side-specific enhancer (ASE). The transcription factor FAST2, which can mediate signaling by TGF beta and activin, has now been identified as a protein that binds to a conserved sequence in ASE. These FAST2 binding sites were both essential and sufficient for L-R asymmetric gene expression. The Fast2 gene is bilaterally expressed when nodal and lefty2 are expressed on the left side. TGF beta and activin can activate the ASE activity in a FAST2-dependent manner, while Nodal can do so in the presence of an EGF-CFC protein. These results suggest that the asymmetric expression of lefty2 and nodal is induced by a left side-specific TGF beta-related factor, which is most likely Nodal itself.
Mol Cell 2000 Jan
PMID:Left-right asymmetric expression of lefty2 and nodal is induced by a signaling pathway that includes the transcription factor FAST2. 1067 67

The sequence evolution of the nuclear gene wingless was investigated among 34 representatives of three lepidopteran families (Riodinidae, Lycaenidae, and Nymphalidae) and four outgroups, and its utility for inferring phylogenetic relationships among these taxa was assessed. Parsimony analysis yielded a well-resolved topology supporting the monophyly of the Riodinidae and Lycaenidae, respectively, and indicating that these two groups are sister lineages, with strong nodal support based on bootstrap and decay indices. Although wingless provides robust support for relationships within and between the riodinids and the lycaenids, it is less informative about nymphalid relationships. Wingless does not consistently recover nymphalid monophyly or traditional subfamilial relationships within the nymphalids, and nodal support for all but the most recent branches in this family is low. Much of the phylogenetic information in this data set is derived from first- and second-position substitutions. However, third positions, despite showing uncorrected pairwise divergences up to 78%, also contain consistent signal at deep nodes within the family Riodinidae and at the node defining the sister relationship between the riodinids and lycaenids. Several hypotheses about how third-position signal has been retained in deep nodes are discussed. These include among-site rate variation, identified as a significant factor by maximum likelihood analyses, and nucleotide bias, a prominent feature of third positions in this data set. Understanding the mechanisms which underlie third-position signal is a first step in applying appropriate models to accommodate the specific evolutionary processes involved in each lineage.
Mol Biol Evol 2000 May
PMID:Molecular evolution of the wingless gene and its implications for the phylogenetic placement of the butterfly family Riodinidae (Lepidoptera: papilionoidea). 1077 29

During atrial fibrillation, ventricular rate is determined by atrioventricular nodal (AVN) conduction, which in part is dependent upon the refractoriness of single AVN cells. The aims of this study were to investigate the rate-dependency of the action potential duration (APD) and effective refractory period (ERP) in single myocytes isolated from the AV node and atrium of rabbit hearts, using whole cell patch clamping, and to determine the contribution of the 4-aminopyridine (4-AP)-sensitive current, I(TO1)to these relationships in the two cell types. AVN cells had a more positive maximum diastolic potential (-60+/-1 v-71+/-2 mV), lower V(max)(8+/-2 v 144+/-17 V/s) and higher input resistance [420+/-46 v 65+/-7 MOmega (mean+/-s.eP<0.05 n=9-33)], respectively, than atrial myocytes. Stepwise increases in rate from 75 beats/min caused activation failure and Wenckebach periodicity in AVN cells (at around 400 beats/min), but 1:1 activation in atrial cells (at up to 600 beats/min). Rate reduction from 300 to 75 beats/min shortened the ERP in both cell types (from 155+/-7 to 135+/-11 ms in AVN cells [P<0.05, n=6] and from 130+/-8 to 106+/-7 ms in atrial cells [P<0.05, n=10]). Rate increase from 300 to 480 and 600 beats/min shortened ERP in atrial cells, by 12+/-4% (n=8) and 26+/-7% (n=7), respectively (P<0.05). By contrast, AVN ERP did not shorten at rates >300 beats/min. In atrial cells, rate reduction to 75 beats/min caused marked shortening of APD(50)(from 51+/-6 to 29+/-6 ms, P<0. 05). 4-AP (1 m m) significantly prolonged atrial APD(50)at 75 beats/min (P<0.05, n=7), but not at 300 or 400 beats/min. In AVN cells, in contrast, there was less effect of rate change on APD, and 4-AP did not alter APD(50)at any rate. 4-AP also did not affect APD(90)or ERP in either cell type. In conclusion, a lack of ERP-shortening at high rates in rabbit single AVN cells may contribute to ventricular rate control. I(TO1)contributed to the APD(50)rate relation in atrial, but not AVN cells and did not contribute to the ERP rate relation in either cell type.
J Mol Cell Cardiol 2000 Aug
PMID:Rate-dependency of action potential duration and refractoriness in isolated myocytes from the rabbit AV node and atrium. 1090 Jan 78

Cancer invasion is induced by several proteolytic enzyme systems associated with the destruction of basement membrane and extracellular matrix. Urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) have been reported as prognostic factors in breast cancer patients and plasminogen activation is regulated by various factors such as uPAR and growth factors. Thus, we examined the tissue levels of urokinase-type plasminogen activator receptor (uPAR) in breast cancer patients. Tissue uPAR levels were measured by ELISA assay in 268 breast cancer patients. The median and mean values of tissue uPAR level in breast cancer were 3.5 ng/mg cytosol protein and 4.8+/-3.6 ng/mg cytosol protein, respectively. Tissue uPAR level was the highest in T1 stage, but there was no statistical significance between the T stages (p>0.05), nor in nodal stage, in the value of uPAR according to progression. And the value of uPAR expression was not associated with estrogen and progesterone receptor status, number of involved node and percent of node involvement. In TNM stage, tissue uPAR levels were higher in patients with stage I-II than in patients with stage III-IV (p=0.027). In univariate analysis, nodal factor (p=0.002) and TNM stage (p=0.0004) were significant. But, multivariate analysis showed that TNM stage was the only significant prognostic factor (p=0.0002). These results suggest that uPAR is mainly associated with initial tumor invasion and other factors might be involved in later stages of cancer progression.
Int J Mol Med 2000 Sep
PMID:Tissue urokinase-type plasminogen activator receptor levels in breast cancer. 1093 93

We hypothesized that nitric oxide (NO) plays an important role in mediating the anti-adrenergic effect of adenosine on atrioventricular (AV) nodal conduction. In guinea-pig hearts instrumented for measurement of AV nodal conduction time (atrium-to-His bundle, A-H, interval), the NO synthase (NOS) inhibitor, l-NMMA (100 microm), reversibly inhibited 80% (P=0.009, n=6) of adenosine's anti-adrenergic action on the positive dromotropic effect of isoproterenol (0.01 microm). In parallel studies carried out in rabbit AV nodal myocytes, intracellular mechanisms whereby NO mediates the inhibitory effect of adenosine on isoproterenol-induced A-H interval shortening were studied. Adenosine (3 microm) inhibited isoproterenol-stimulated (0.1 microm) I(Ca,L)(beta -I(Ca,L)) by 46+/-6% (P<0.001, n=17). Consistent with isolated heart data, the NOS inhibitors, l -NMMA (100 microm) and L-NNA (500 microm) attenuated the effect of adenosine on beta -I(Ca,L)by 69+/-8% (P<0.001, n=16) and 69+/-7% (P<0.001, n=10), respectively. An inhibitor of NO-stimulated guanylyl cyclase LY83538 (40 microm) reduced the inhibitory effect of adenosine on beta -I(Ca,L)by 97+/-6% (P=0.004, n=15). Similarly, the non-specific inhibitor of cAMP-phosphodiesterases IBMX (50 microm) decreased the anti-adrenergic effect of adenosine by 60% (P=0.02, n=6), whereas the extracellular application of the non-hydrolyzeable cAMP analog 8-Br-cAMP (500 microm) prevented this action of adenosine. Activation of cGMP-dependent protein kinase (PKG) by CPT-cGMP (300 microm) diminished beta -I(Ca,L), but to a significantly smaller degree (16+/-4%, P=0.025, n=12) than that caused by adenosine. NO mediates the anti-adrenergic effect of adenosine on AV nodal conduction by a mechanism predominately involving activation of cGMP-dependent cAMP-phosphodiesterase and to a lesser extent activation of PKG.
J Mol Cell Cardiol 2000 Sep
PMID:Antagonism of the positive dromotropic effect of isoproterenol by adenosine: role of nitric oxide, cGMP-dependent cAMP-phosphodiesterase and protein kinase G. 1096 24

Control of proliferation and differentiation by the retinoblastoma tumor suppressor protein (pRB) and related family members depends upon their interactions with key cellular substrates. Efforts to identify such cellular targets led to the isolation of a novel protein, EID-1 (for E1A-like inhibitor of differentiation 1). Here, we show that EID-1 is a potent inhibitor of differentiation and link this activity to its ability to inhibit p300 (and the highly related molecule, CREB-binding protein, or CBP) histone acetylation activity. EID-1 is rapidly degraded by the proteasome as cells exit the cell cycle. Ubiquitination of EID-1 requires an intact C-terminal region that is also necessary for stable binding to p300 and pRB, two proteins that bind to the ubiquitin ligase MDM2. A pRB variant that can bind to EID1, but not MDM2, stabilizes EID-1 in cells. Thus, EID-1 may act at a nodal point that couples cell cycle exit to the transcriptional activation of genes required for differentiation.
Mol Cell Biol 2000 Dec
PMID:Cells degrade a novel inhibitor of differentiation with E1A-like properties upon exiting the cell cycle. 1107 89

Histochemical analyses of type II brain 4.1/4.1B/KIAA0987, a member of the protein 4.1 family, were carried out in rat brain. In situ hybridization (ISH) showed that type II brain 4.1 mRNA is expressed in a variety of neuronal cells. In particular, type II brain 4.1 mRNA was actively transcribed in the cells of the mesencephalon and the brainstem, which have large myelinated nerve fibers. Expression of type II brain 4.1 mRNA was not observed at least in glial cells distributed in nerve fiber tracts. In immunohistochemical studies using anti-type II brain 4.1-specific antibody, the major immunosignals appeared as brilliant pairs of dots along nerve fibers. Such immunosignals were detected throughout the brain, but were highly concentrated in nerve fiber tracts. These data suggested that type II brain 4.1 is predominantly localized to neuronal paranodes. Detailed analysis concentrating on the nodal region indicated that type II brain 4.1 is present at the paranodal membrane but not in the axoplasm. Weaker type II brain 4.1-specific immunosignals were observed along the internodal membrane of myelinated axons and in the cytoplasm of some neuronal cells. Finally, comparative immunohistochemical studies using antibodies against the other three protein 4.1 family members, type I brain 4.1/4.1N/KIAA0338, erythroid type 4.1 (4.1R) and 4.1G, demonstrated that each of these proteins is distributed in a unique pattern in the cerebellum. Our results are the first to show that type II brain 4.1 is the only member of the protein 4.1 family localized to neuronal paranodes.
Brain Res Mol Brain Res 2000 Dec 28
PMID:Type II brain 4.1 (4.1B/KIAA0987), a member of the protein 4.1 family, is localized to neuronal paranodes. 1114 5


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