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

We present evidence that LIM kinases can control cell adhesion and compaction in human epidermis. LIMK2 is expressed in the epidermal basal layer and signals downstream of the GTPase Rac1 to promote extracellular matrix adhesion and inhibit terminal differentiation. Conversely, LIMK1 is expressed in the upper granular layers and phosphorylates and inhibits cofilin. Expression of LIMK1 is lost in psoriatic lesions and other skin disorders characterized by lack of cell compaction in the differentiating cell layers. In psoriatic lesions down-regulation of LIMK1 correlates with up-regulation of Myc. Expression of constitutively active cofilin or Myc in reconstituted human epidermis blocks cell compaction. Overexpression of LIMK1 leads to down-regulation of Myc, whereas inhibition of Rho kinase, an upstream activator of LIMK1, stimulates Myc expression. Inhibition of Myc by LIMK1 is via inhibition of Stat3 phosphorylation, because constitutively active cofilin or inhibition of Rho kinase results in Stat3 phosphorylation and increased Myc levels, whereas dominant negative Stat3 abolishes the effect. In conclusion, we have uncovered a novel antagonistic relationship between the LIMK1/phosphocofilin and Myc/Stat3 pathways in the differentiating layers of human epidermis and propose that down-regulation of LIMK1 contributes to one of the pathological features of psoriatic epidermal lesions.
Mol Biol Cell 2006 Apr
PMID:Role of LIM kinases in normal and psoriatic human epidermis. 1646 74

Given the well-defined role of LIM-motif containing proteins in cytoskeletal organization, cell fate, and differentiation, we hypothesized that the regulation of LIM proteins played an integral role in vascular remodeling. We screened a compendium of cDNA microarray data from rat vascular smooth muscle cells (VSMC) for novel LIM-containing targets and identified muscle LIM protein (MLP), a gene previously thought to be only in striated muscle. Sequence analysis, RTQPCR and Western blotting reconfirmed expression of MLP in VSMC. MLP was elevated>10-fold 7 days following balloon injury in the rat carotid artery. Wire injury led to a significantly increased intima/media ratio in MLP -/- mice compared to wild-type controls (P<0.007, N=5). Fas-ligand and ceramide-induced apoptosis were significantly decreased in MLP deficient VSMC (n=6, P<0.001). Adenoviral-induced restoration of MLP significantly restored apoptotic response (N=6, P<0.001). These findings are the first to identify MLP in vascular smooth muscle and demonstrate that it plays a critical role in vascular remodeling. This is consistent with earlier findings demonstrating a role for MLP in striated muscle remodeling in response to load and stretch.
J Mol Cell Cardiol 2006 Apr
PMID:A role for muscle LIM protein (MLP) in vascular remodeling. 1651 96

The MYND domain (named after myeloid translocation protein 8, Nervy, and DEAF-1) is a conserved zinc binding domain. It is defined by seven conserved cysteine residues and a single histidine residue that are arranged in a C4-C2HC consensus. MYND domains exist in a large number of proteins that play important roles in development or are associated with cancers and have been shown to mediate protein-protein interactions, mainly in the context of transcriptional regulation. We have determined the three-dimensional structure of the MYND domain from human deformed epidermal autoregulatory factor-1 (DEAF-1). The structure reveals a novel zinc binding fold, in which the C4-C2HC motif forms two sequential zinc binding sites. The first and second zinc binding modules comprise a small beta hairpin and two short alpha helices, respectively. The sequential topology of the two zinc binding sites is distinct from the cross-brace PHD and RING finger folds but has some resemblance to LIM domains. The structure reveals that the MYND domain is a novel member of the treble-clef family of zinc binding domains. The MYND domains of BS69 and BOP bind ligands comprising a PXLXP peptide motif. On the basis of the solution structure of the DEAF-1 MYND domain we calculated a homology model of the MYND domain of the BS69 tumor suppressor. A mutational analysis of the BS69 MYND domain indicates that positively charged residues located on one face of its MYND domain are crucial for the molecular interactions of BS69. Different binding specificities of MYND domains may depend on distinct surface charge distributions.
J Mol Biol 2006 Apr 28
PMID:Structure and functional analysis of the MYND domain. 1828 14

Cholangiocarcinoma (CCA) induced by liver fluke (Opisthorchis viverrini, Ov) infection is one of the most common and serious disease in northeast Thailand. To elucidate the molecular mechanism of cholangiocarcinogenesis induced by Ov infection, we employed a hamster model of CCA induced by Ov and N-nitrosodimethylamine and analyzed candidate genes involved in CCA using fluorescence differential display-PCR. Of 149 differentially amplified bands we identified, the upregulation of 23 transcripts and downregulation of 1 transcript related to CCA hamsters were confirmed by a reverse northern macroarray blot. The upregulated genes include signal transduction protein kinase A regulatory subunit Ialpha (Prkar1a), myristoylated alanine-rich protein kinase C substrate, transcriptional factor LIM-4-only domain, oxysterol-binding protein involved in lipid metabolism, splicing regulatory protein 9, ubiquitin conjugating enzyme involved in protein degradation, beta tubulin, beta actin, and collagen type VI. Quantitative real-time PCR confirmed that the expression of Prkar1a was significantly higher in CCA and its precursor lesion when compared with normal liver and normal gall bladder epithelia (P<0.05). Prkar1a expression tended to increase along with the progression of biliary transformation from hyperplasia and precancerous lesions to carcinoma. These findings contribute to our understanding of the processes involved in the molecular carcinogenesis of CCA in order to provide a unique perspective on the development of new chemotherapeutics in future.
Mol Carcinog 2006 May
PMID:Altered gene expression in Opisthorchis viverrini-associated cholangiocarcinoma in hamster model. 1655 Jun 11

The GnRH receptor (GnRH-R) plays a central role in mammalian reproductive function throughout adulthood. It also appears as an early marker gene of the presumptive gonadotrope lineage in developing pituitary. Here, using transient transfections combined with DNA/protein interaction assays, we have delineated cis-acting elements within the rat GnRH-R gene promoter that represent targets for the LIM-homeodomain (LIM-HD) proteins, Isl-1 and Lhx3. These factors, critical in early pituitary development, are thus also crucial for gonadotrope-specific expression of the GnRH-R gene. In heterologous cells, the expression of Isl-1 and Lhx3, together with steroidogenic factor 1 (SF-1), culminates in the activation of both the rat as well as human GnRH-R promoter, suggesting that this combination is evolutionarily conserved among mammals. The specificity of these LIM-HD factors is attested by the inefficiency of related proteins, including Lhx5 and Lhx9, to activate the GnRH-R gene promoter, as well as by the repressive capacity of a dominant-negative derivative of Lhx3. Accordingly, targeted deletion of the LIM response element decreases promoter activity. In addition, experiments with Gal4-SF-1 fusion proteins suggest that LIM-HD protein activity in gonadotrope cells is dependent upon SF-1 binding. Finally, using a transgenic model that allows monitoring of in vivo promoter activity, we show that the overlapping expression of Isl-1 and Lhx3 in the developing pituitary correlates with promoter activity. Collectively, these data suggest the occurrence of a specific LIM-HD pituitary code and designate the GnRH-R gene as the first identified transcriptional target of Isl-1 in the anterior pituitary.
Mol Endocrinol 2006 Sep
PMID:The LIM-homeodomain proteins Isl-1 and Lhx3 act with steroidogenic factor 1 to enhance gonadotrope-specific activity of the gonadotropin-releasing hormone receptor gene promoter. 1661 90

The overexpression of LIM-only protein 2 (LMO2) in T-cells, as a result of chromosomal translocations, retroviral insertion during gene therapy, or in transgenic mice models, leads to the onset of T-cell leukemias. LMO2 comprises two protein-binding LIM domains that allow LMO2 to interact with multiple protein partners, including LIM domain-binding protein 1 (Ldb1, also known as CLIM2 and NLI), an essential cofactor for LMO proteins. Sequestration of Ldb1 by LMO2 in T-cells may prevent it binding other key partners, such as LMO4. Here, we show using protein engineering and enzyme-linked immunosorbent assay (ELISA) methodologies that LMO2 binds Ldb1 with a twofold lower affinity than does LMO4. Thus, excess LMO2 rather than an intrinsically higher binding affinity would lead to sequestration of Ldb1. Both LIM domains of LMO2 are required for high-affinity binding to Ldb1 (K(D) = 2.0 x 10(-8) M). However, the first LIM domain of LMO2 is primarily responsible for binding to Ldb1 (K(D) = 2.3 x 10(-7) M), whereas the second LIM domain increases binding by an order of magnitude. We used mutagenesis in combination with yeast two-hybrid analysis, and phage display selection to identify LMO2-binding "hot spots" within Ldb1 that locate to the LIM1-binding region. The delineation of this region reveals some specific differences when compared to the equivalent LMO4:Ldb1 interaction that hold promise for the development of reagents to specifically bind LMO2 in the treatment of leukemia.
J Mol Biol 2006 May 26
PMID:Identification of the key LMO2-binding determinants on Ldb1. 1661 88

APS (adaptor protein with PH and SH2 domains) initiates a phosphatidylinositol 3-kinase-independent pathway involved in insulin-stimulated glucose transport. We recently identified Enigma, a PDZ and LIM domain-containing protein, as a partner of APS and showed that APS-Enigma complex plays a critical role in actin cytoskeleton organization in fibroblastic cells. Because actin rearrangement is important for insulin-induced glucose transporter 4 (Glut 4) translocation, we studied the potential involvement of Enigma in insulin-induced glucose transport in 3T3-L1 adipocytes. Enigma mRNA was expressed in differentiated adipocytes and APS and Enigma were colocalized with cortical actin. Expression of an APS mutant unable to bind Enigma increased the insulin-induced Glut 4 translocation to the plasma membrane. By contrast, overexpression of Enigma inhibited insulin-stimulated glucose transport and Glut 4 translocation without alterations in proximal insulin signaling. This inhibitory effect was prevented with the deletion of the LIM domains of Enigma. Using time-lapse fluorescent microscopy of green fluorescent protein-actin, we demonstrated that the overexpression of Enigma altered insulin-induced actin rearrangements, whereas the expression of Enigma without its LIM domains was without effect. A physiological link between increased expression of Enigma and an alteration in insulin-induced glucose uptake was suggested by the increase in Enigma mRNA expression in adipose tissue of diabetic obese patients. Taken together, these data strongly suggest that the interaction between APS and Enigma is involved in insulin-induced Glut 4 translocation by regulating cortical actin remodeling and raise the possibility that modification of APS/Enigma ratio could participate in the alteration of insulin-induced glucose uptake in adipose tissue.
Mol Endocrinol 2006 Nov
PMID:Enigma interacts with adaptor protein with PH and SH2 domains to control insulin-induced actin cytoskeleton remodeling and glucose transporter 4 translocation. 1680 68

Entamoeba histolytica is a protozoan intestinal parasite that causes amoebic colitis and amoebic liver abscess. To identify virulence factors of E. histolytica, we first defined the phenotypes of two E. histolytica strains, HM-1:IMSS, the prototype virulent strain, and E. histolytica Rahman, a strain that was reportedly less virulent than HM-1:IMSS. We found that compared with HM-1:IMSS, Rahman has a defect in erythrophagocytosis and the ability to cause amoebic colitis in human colonic xenografts. We used differential in-gel 2D electrophoresis to compare the proteome of Rahman and HM-1:IMSS, and identified six proteins that were differentially expressed above a fivefold level between the two organisms. These included two proteins with antioxidative properties (peroxiredoxin and superoxide dismutase), and three proteins of unknown function, grainin 1, grainin 2 and a protein containing a LIM-domain. Overexpression of peroxiredoxin in Rahman rendered the transgenic trophozoites more resistant to killing by H2O2 in vitro, and infection with Rahman trophozoites expressing higher levels of peroxiredoxin was associated with higher levels of intestinal inflammation in human colonic xenografts, and more severe disease based on histology. In contrast, higher levels of grainin appear to be associated with a reduced virulence phenotype, and E. histolytica HM-1:IMSS trophozoites infecting human intestinal xenografts show marked decreases in grainin expression. Our data indicate that there are definable molecular differences between Rahman and HM-1:IMSS that may explain the phenotypic differences, and identify peroxiredoxin as an important component of virulence in amoebic colitis.
Mol Microbiol 2006 Sep
PMID:Comparative proteomic analysis of two Entamoeba histolytica strains with different virulence phenotypes identifies peroxiredoxin as an important component of amoebic virulence. 1696 25

The orphan nuclear receptor HNF4alpha and the LIM homeodomain factor Isl1 are co-expressed in pancreatic beta-cells and are required for the differentiation and function of these endocrine cells. HNF4alpha activates numerous genes and mutations in its gene are associated with maturity onset diabetes of the young. Cofactors and transcription factors that interact with HNF4alpha are crucial to modulate its transcriptional activity, since the latter is not regulated by conventional ligands. These transcriptional partners interact mainly through the HNF4alpha AF-1 module and the ligand binding domain, which contains the AF-2 module. Here, we showed that Isl1 could enhance the HNF4alpha-mediated activation of transcription of the HNF1alpha, PPARalpha and insulin I promoters. Isl1 interacted with the HNF4alpha AF-2 but also required the HNF4alpha carboxy-terminal F domain for optimal interaction and transcriptional synergy. More specifically, we found that naturally occurring HNF4alpha isoforms, differing only in their F domain, exhibited different abilities to interact and synergize with Isl1, extending the crucial transcriptional modulatory role of the HNF4alpha F domain. HNF4alpha interacted with both the homeodomain and the first LIM domain of Isl1. We found that the transcriptional synergy between HNF4alpha and Isl1 involved an increase in HNF4alpha loading on promoter. The effect was more pronounced on the rat insulin I promoter containing binding sites for both HNF4alpha and Isl1 than on the human HNF1alpha promoter lacking an Isl1 binding site. Moreover, Isl1 could mediate the recruitment of the cofactor CLIM2 resulting in a further transcriptional enhancement of the HNF1alpha promoter activity.
J Mol Biol 2006 Dec 08
PMID:Hepatocyte nuclear factor 4 alpha ligand binding and F domains mediate interaction and transcriptional synergy with the pancreatic islet LIM HD transcription factor Isl1. 1702 98

The LIM-homeodomain (LIM-HD) proteins have a homeodomain and two N-terminal LIM domains, which consist of a conserved cysteine- and histidine-rich structure of two tandem repeated zinc fingers. LIM domain is involved in protein-protein interactions during transcriptional regulation. LIM-HD proteins are classically suggested as major transcriptional regulators which, in cooperation with other transcription factors, play critical roles in several developing systems and organs, such as nervous system, pancreas, and heart. Here we have cloned the full-length cDNA of human Isl-2 from a human embryo heart cDNA library. The gene contains six exons and spans 5.7 kb in chromosome 15q23 region, and transcribes a 1.9 kb mRNA that encodes a protein with 359 amino acid residues. The predicted protein, containing two tandem LIM motifs in N-terminal and a homeodomain domain, is well conserved, especially in the LIM and DNA-binding domains. Northern blot analysis shows that human Isl-2 is expressed in every human tissue examined at adult stage and during embryonic developmental stages from 34 days to 24 weeks at different levels in tissues. The broad expression of Isl-2 gene in tissues during embryogenesis and adult development suggests that it may be involved in both differentiation and maintenance of these tissues and might play an important role.
Mol Biol Rep 2007 Mar
PMID:Cloning and expression of a novel human gene, Isl-2, encoded a LIM-homeodomain protein. 1709 38


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