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

The gonadotrope-specific and regulated expression of the GnRH receptor (GnRH-R) gene is dependent on multiple transcription factors that interact with the noncanonical GnRH-R activating sequence (GRAS), the activator protein-1 (AP-1) element, and the steroidogenic factor-1 (SF-1) binding site. However, these three elements are not sufficient to mediate the complete cell-specific expression of the rat GnRH-R gene. In the present study, we demonstrate, by transient transfection in gonadotrope-derived alphaT3-1 and LssT2 cell lines, the existence of a distal enhancer [GnRH-R- specific enhancer (GnSE)] that is highly active in the context of the GnRH-R gene promoter. We show that the GnSE activity (-1,135/-753) is mediated through a functional interaction with a proximal region (-275/-226) that includes the SF-1 response element. Regions of similar length containing either the AP-1 or GRAS elements are less active or inactive. Transfection assays using an artificial promoter containing two SF-1 elements fused to a minimal PRL promoter indicate that SF-1 is crucial in this interaction. In addition, by altering the promoter with deletion and block- replacement mutations, we have identified the active elements of GnSE within two distinct sequences at positions -983/-962 and -871/-862. Sequence analysis and electrophoretic mobility shift experiments suggest that GnSE response elements interact, in these two regions, with GATA- and LIM-related factors, respectively. Altogether, these data establish the importance of the GnSE in the GnRH-R gene expression and reveal a novel role for SF-1 as a mediator of enhancer activity, a mechanism that might regulate other SF-1 target genes.
Mol Endocrinol 2001 Feb
PMID:Proximal cis-acting elements, including steroidogenic factor 1, mediate the efficiency of a distal enhancer in the promoter of the rat gonadotropin-releasing hormone receptor gene. 1115 37

The transcription factor Pax6 is expressed in discrete domains in the developing brain, generally limited to progenitor populations. However, in the embryonic mouse diencephalon, Pax6 is not only expressed in neuroepithelial progenitors, but also at high levels in a specific set of initial neurons. These neurons first appeared on embryonic day 9.5 (E9.5) in the presumptive ventral thalamus and were fated to become A13 dopaminergic neurons of the medial zona incerta. To further characterize the initial differentiation of these neurons, and the function of Pax6 in their formation, the expression patterns of a number of transcription factors were described. The progenitor population was defined by reciprocal overlapping expression gradients of Pax6 and Nkx2.2, and a subset of proliferating progenitors were labeled with an antibody against DLX transcription factors. The initial neurons expressed combinations of transcription factors, including Pax6, DLX, and the LIM-domain proteins islet-1, Lhx1 (Lim1), and Lhx5 (Lim-2). Bromo-deoxyuridine (BrdU) labeling was used to follow the fate of a cohort of proliferating cells, defining a step-wise sequence of gene activation during differentiation. Pax6 up-regulation occurred only several hours postdifferentiation. The loss of Pax6 altered progenitor specification, and the Lhx1 neuronal marker was lost, indicating a role for Pax6 in the specification of forebrain neuron identity.
Mol Cell Neurosci 2001 Jan
PMID:Pax6 regulates the identity of embryonic diencephalic neurons. 1116 79

The actinin-associated LIM protein, ALP, is the prototype of a large family of proteins containing an N-terminal PDZ domain and a C-terminal LIM domain. These PDZ-LIM proteins are components of the muscle cytoskeleton and occur along the Z lines owing to interaction of the PDZ domain with the spectrin-like repeats of alpha-actinin. Because PDZ and LIM domains are typically found in proteins that mediate cellular signaling, PDZ-LIM proteins are suspected to participate in muscle development. Interestingly the ALP gene occurs at 4q35 near the heterochromatic region mutated in facioscapulohumeral muscular dystrophy, indicating a possible role for ALP in this disease. Here, we describe the generation and analysis of mice lacking the ALP gene. Surprisingly, the ALP knockout mice show no gross histological abnormalities and maintain sarcolemmal integrity as determined by serum pyruvate kinase assays. The absence of a dystrophic phenotype in these mice suggests that down-regulation of ALP does not participate in facioscapulohumeral muscular dystrophy. These data suggest that ALP does not participate in muscle development or that an alternative PDZ-LIM protein can compensate for the lack of ALP.
Mol Cell Biol 2001 Mar
PMID:Actinin-associated LIM protein-deficient mice maintain normal development and structure of skeletal muscle. 1123 5

Testicular protein kinase 1 (TESK1) is a serine/threonine kinase with a structure composed of a kinase domain related to those of LIM-kinases and a unique C-terminal proline-rich domain. Like LIM-kinases, TESK1 phosphorylated cofilin specifically at Ser-3, both in vitro and in vivo. When expressed in HeLa cells, TESK1 stimulated the formation of actin stress fibers and focal adhesions. In contrast to LIM-kinases, the kinase activity of TESK1 was not enhanced by Rho-associated kinase (ROCK) or p21-activated kinase, indicating that TESK1 is not their downstream effector. Both the kinase activity of TESK1 and the level of cofilin phosphorylation increased by plating cells on fibronectin. Y-27632, a specific inhibitor of ROCK, inhibited LIM-kinase-induced cofilin phosphorylation but did not affect fibronectin-induced or TESK1-induced cofilin phosphorylation in HeLa cells. Expression of a kinase-negative TESK1 suppressed cofilin phosphorylation and formation of stress fibers and focal adhesions induced in cells plated on fibronectin. These results suggest that TESK1 functions downstream of integrins and plays a key role in integrin-mediated actin reorganization, presumably through phosphorylating and inactivating cofilin. We propose that TESK1 and LIM-kinases commonly phosphorylate cofilin but are regulated in different ways and play distinct roles in actin reorganization in living cells.
Mol Biol Cell 2001 Apr
PMID:Cofilin phosphorylation by protein kinase testicular protein kinase 1 and its role in integrin-mediated actin reorganization and focal adhesion formation. 1129 12

IGF-II is an autocrine growth factor for many colon cancer cells. This study aimed to determine the role of IGF-II in proliferation and adhesion of LIM 1215 colon cancer cells. RT-PCR demonstrated expression of IGF-I and IGF-II mRNA. Addition of IGF-I or -II increased monolayer proliferation in a dose-dependent manner. Although addition of IGFBP-6 had no effect on basal proliferation, coincubation of IGFBP-6 decreased IGF-II but not IGF-I-induced proliferation. Colony formation in agar was increased by IGF-II, an effect inhibited by coincubation with IGFBP-6. IGFBP-6 alone significantly decreased colony formation. Preincubation of cells with IGF-II increased adhesion to type IV collagen, fibronectin and laminin. IGFBP-6 had no effect on basal cell adhesion but completely inhibited the effects of IGF-II. LIM 1215 colon cancer cells are therefore IGF-responsive but IGF-II is not a major autocrine factor for these cells in monolayer, suggesting heterogeneity between colon carcinoma cell lines with respect to the role of the IGF system.
Mol Cell Endocrinol 2001 Mar 28
PMID:Insulin-like growth factor (IGF)-binding protein-6 inhibits IGF-II-induced but not basal proliferation and adhesion of LIM 1215 colon cancer cells. 1130 78

It is becoming increasingly evident that proteins of the actin depolymerizing factor (ADF)/cofilin family are essential regulators of actin turnover required for many actin-based cellular processes, including motility. ADF can increase actin turnover by either increasing the rate of actin filament treadmilling or by severing actin filaments. In neurons ADF is highly expressed in neuronal growth cones and its activity is regulated by many signals that affect growth cone motility. In addition, increased activity of ADF causes an increase in neurite extension. ADF activity is inhibited upon phosphorylation by LIM kinases (LIMK), kinases activated by members of the Rho family of small GTPases. ADF become dephosphorylated downstream of signal pathways that activate PI-3 kinase or increase levels of intracellular calcium. The growth-regulating effects of ADF together with its ability to be regulated by a wide variety of guidance cues, suggest that ADF may regulate growth cone advance and navigation.
Mol Neurobiol
PMID:Signal-regulated ADF/cofilin activity and growth cone motility. 1132 52

The gene CREM plays key physiological and developmental roles within the hypothalamic--pituitary--gonadal axis. We have previously shown that CREM is highly expressed in male postmeiotic cells. Spermiogenesis is a complex process by which postmeiotic male germ cells differentiate into mature spermatozoa. CREM regulates the expression of a number of post-meiotic genes involved in the process of spermiogenesis. Using homologous recombination we have generated CREM-mutant mice that display a complete block at the first step of spermiogenesis. The molecular mechanism by which CREM elicits its regulatory function involves ACT (Activator of CREM in Testis), a testis-specific coactivator constituted by a repeat of four and half LIM domains. ACT is coordinately expressed with CREM, associates with it and confers a powerful transcriptional activation function. It is able to bypass the classical requirement of CREM phosphorylation and recruiting of CBP.
Mol Cell Endocrinol 2001 Jun 20
PMID:Transcriptional cascades during spermatogenesis: pivotal role of CREM and ACT. 1142 Jan 26

We have identified a novel LIM gene encoding the thymus LIM protein (TLP), expressed specifically in the thymus in a subset of cortical epithelial cells. TLP was identified as a gene product which is upregulated in a thymus in which selection of T cells is occurring (Rag(-/-) OT-1) compared to its expression in a thymus in which selection is blocked at the CD4+ CD8+ stage of T-cell development (Rag(-/-) Tap(-/-) OT-1). TLP has an apparent molecular mass of 23 kDa and exists as two isomers (TLP-A and TLP-B), which are generated by alternative splicing of the message. The sequences of TLP-A and TLP-B are identical except for the C-terminal 19 or 20 amino acids. Based on protein sequence alignment, TLP is most closely related to the cysteine-rich proteins, a subclass of the family of LIM-only proteins. In both medullary and cortical thymic epithelial cell lines transduced with TLP, the protein localizes to the cytoplasm but does not appear to be strongly associated with actin. In immunohistochemical studies, TLP seems to be localized in a subset of epithelial cells in the cortex and is most abundant near the corticomedullary junction. We generated mice with a targeted disruption of the Tlp locus. In the absence of TLP, thymocyte development and thymus architecture appear to be normal but thymocyte cellularity is reduced by approximately 30%, with a proportional reduction in each subpopulation.
Mol Cell Biol 2001 Dec
PMID:Identification and characterization of thymus LIM protein: targeted disruption reduces thymus cellularity. 1171 92

The LIM domain is a cysteine-rich zinc-finger motif found in a large family of proteins. In LIM-homeodomain (LIM-hd) transcription factors and LIM-only (LMO) factors, the LIM domains are responsible for key interactions with co-activators, co-repressors, competitors, and other transcription factors, and are therefore of considerable importance for the regulation of associated transcriptional activity. In this review, the authors describe the progressive discoveries of NLI/Ldb/CLIM, LMO and RLIM, and discuss how the field was very recently updated by the finding that LIM-hd transcriptional activity is controlled by regulated degradation of cofactors and LIM-hd themselves.
Mol Neurobiol
PMID:A short history of LIM domains (1993-2002): from protein interaction to degradation. 1242 60

Pituitary dwarfism in the German shepherd dog is an autosomal recessive inherited abnormality. We tested the hypothesis that a variant of the LIM homeodomain gene LHX4 is responsible for the dwarfism phenotype. To this end, we isolated Bacterial Artificial Chromosome clones for the canine LHX4 gene. Southern blotting experiments showed that the LHX4 gene is a single copy gene in the canine genome. A complex CA-repeat was isolated from the BAC clones and was found to be polymorphic in German shepherd dogs. Genotyping 5 litters in which the dwarfism was segregating showed disconcordance between the inheritance of the dwarfism phenotype and the DNA marker. It is concluded that the LHX4 gene does not play a primary role in the pituitary dwarfism in the German shepherd dogs.
Mol Cell Endocrinol 2002 Nov 29
PMID:Exclusion of the lim homeodomain gene LHX4 as a candidate gene for pituitary dwarfism in German shepherd dogs. 1243 96


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