Dab2 mRNA Research Articles

Synergistic Induction of DOC-2/DAB2 Gene Expression in Transitional Cell Carcinoma in the Presence of GATA6 and Histone Deacetylase Inhibitor

The down-regulation of DOC-2/DAB2 gene, which encodes a unique phosphoprotein modulating signal pathways elicited by exogenous stimuli, is often associated with several cancer types; however, the underlying mechanism is still unknown. Dramatically different expression levels of DOC-2/DAB2 mRNA and protein are observed among several human transitional cell carcinoma (TCC) cell lines, suggesting that transcriptional regulation may play a role in these cells. In this study, we have shown that the histone acetylation status associated with the 5' upstream regulatory sequence of DOC-2/DAB2 gene is one of the key determinants for its gene expression. In addition, GATA6 but not other GATA family members, such as GATA2 and GATA4, can specifically induce DOC-2/DAB2 promoter activity, although GATA transcription factors share a very similar DNA-binding sequence. We also show that increased histone acetylation and the presence of GATA6 have a synergistic effect on DOC-2/DAB2 promoter activity, which results in the elevation of DOC-2/DAB2 protein expression. Thus, we conclude that transcriptional regulation of DOC-2/DAB2 gene in human TCC is determined by histone acetylation and a specific transcription factor (i.e., GATA6), which underlie the reduced DOC-2/DAB2 protein expression in TCC cells.

The Cells of Cajal-Retzius: Still a Mystery One Century After

Cajal-Retzius (CR) cells are an enigmatic class of neurons located at the surface of the cerebral cortex, playing a major role in cortical development. In this review, we discuss several distinct features of these neurons and the mechanisms by which they regulate cortical development. Many CR cells likely have extracortical origin and undergo cell death during development. Recent genetic studies report unique patterns of gene expression in CR cells, which may help to explain the developmental processes in which they participate. Moreover, a number of studies indicate that CR cells, and their secreted gene product, reelin, are involved in neuronal migration by acting on two key partners, migrating neurons and radial glial cells. Emerging data show that these neurons are a critical part of an early and complex network of neural activity in layer I, supporting the notion that CR cells modulate cortical maturation. Given these key and complex developmental properties, it is therefore conceivable for CR cells to be implicated in the pathogenesis of a variety of neurological disorders.

Retinoid receptor mRNA expression profiles in human bladder cancer specimens

Retinoids, which include vitamin A (retinol) and its derivatives, have previously been investigated as potential chemopreventive and chemotherapeutic agents in bladder cancer. We examined mRNA expression of the retinoid receptors RARalpha, RARbeta2, RARgamma and RXRalpha, as well as two putative RARbeta2 target genes, DAB2 and Midkine, in normal and malignant bladder tissue specimens from human patients. We evaluated 24 normal and malignant bladder specimens for retinoid receptor, DAB2 and Midkine mRNA expression using RT-PCR. We also examined the effects of retinoic acid and retinol on the expression of these genes in five human bladder cancer cell lines. Expression of RARalpha, RARbeta2, RARgamma and RXRalpha mRNA was detected in all of the non-neoplastic patient bladder specimens. RARbeta2 mRNA expression was undetectable in 7/13 tumors, RARalpha in 3/13, RARgamma in 1/13 and RXRalpha in 2/13. DAB2 mRNA was expressed in all non-neoplastic and all tumor specimens, while Midkine mRNA was detected in 8/11 non-neoplastic specimens versus 11/13 tumors. Two of the five bladder cancer cell lines expressed RARbeta2 independent of retinoid exposure; in three cell lines RARbeta2 expression was induced by retinoids. RARalpha, RARgamma and RXRalpha mRNA expression was detected in 5/5 cell lines, independent of retinoid exposure. We found a reduction in retinoid receptor mRNA expression, particularly for RARbeta2, in human bladder cancer specimens. We also demonstrated induction of RARbeta2 mRNA expression in some of the retinoid-treated bladder cancer cell lines. We suggest that restoration of RARbeta2 expression may be a reasonable biomarker for developing bladder cancer preventive and/or therapeutic drugs.

Reelin signaling is impaired in autism

Autism is a severe neurodevelopmental disorder with genetic and environmental etiologies. Recent genetic linkage studies implicate Reelin glycoprotein in causation of autism. To further investigate these studies, brain levels of Reelin protein and mRNA and mRNAs for VLDLR, Dab-1, and GSK3 were investigated. Postmortem superior frontal, parietal, and cerebellar cortices of age, gender, and postmortem interval-matched autistic and control subjects were subjected to SDS-PAGE and Western blotting of Reelin protein. Quantitative reverse transcriptase polymerase chain reaction analysis of Reelin, VLDL-R, Dab-1, and GSK3 mRNA species in superior frontal and cerebellar cortices of autistic and control subjects were also performed. Reelin 410, 330, and 180 kDa/beta-actin values were reduced significantly in frontal and cerebellar, and nonsignificantly in parietal, areas of autistic brains versus control subjects, respectively. The mRNAs for Reln and Dab-1 were reduced significantly whereas the mRNA for Reln receptor VLDLR was elevated significantly in superior frontal and cerebellar areas of autistic brains versus control brains, respectively. Reductions in Reelin protein and mRNA and Dab 1 mRNA and elevations in Reln receptor VLDLR mRNA demonstrate impairments in the Reelin signaling system in autism, accounting for some of the brain structural and cognitive deficits observed in the disorder.

Disabled‐1 mRNA and protein expression in developing human cortex

Disabled-1 (Dab1) forms part of the Reelin-Dab1 signalling pathway that controls neuronal positioning during brain development; Dab1 deficiency gives rise to a reeler-like inversion of cortical layers. To establish a timetable of Dab1 expression in developing human brain, Dab1 mRNA and protein expression were studied in prenatal human cortex. The earliest Dab1 signal was detected at 7 gestational weeks (GW), the stage of transition from preplate to cortical plate, suggesting a role of the Reelin-Dab1 signalling pathway in preplate partition. From 12 to 20 GW, the period of maximum cortical migration, Dab1 expression was prominent in the upper tiers of the cortical plate, to decline after midgestation. Radially orientated apical dendrites of Dab1-expressing neurons indicated a predominant pyramidal phenotype. Pyramidal cells in hippocampus and entorhinal cortex displayed a more protracted time of Dab1 expression compared to neocortex. In addition, at later stages (18-25 GW), Dab1 was also expressed in large neurons scattered throughout intermediate zone and subplate. From 14 to 22 GW, particularly high levels of Dab1 mRNA and protein were observed in cells of the ventricular/subventricular zone displaying the morphology of radial glia. The partial colocalization of vimentin and Dab1 in cells of the ventricular zone supported a radial glia phenotype. The concentration of Dab1 protein in ventricular endfeet and initial portions of radial processes of ventricular-zone cells points to a possible involvement of Dab1 in neurogenesis. Furthermore, a subset of Cajal-Retzius cells in the marginal zone colocalized Dab1 and Reelin, and may thus represent a novel target of the Reelin-Dab1 signalling pathway.

Induction of Disabled-2 Gene during Megakaryocyte Differentiation of K562 Cells

Megakaryocyte differentiation is often accompanied by the changes of gene expression pattern. Here we reported that the expression of DAB2, a putative adaptor protein in cell signaling, was induced at the protein and mRNA levels upon 12-O-tetradecanoylphorbol-13-acetate-mediated megakaryocyte differentiation of human chronic myeloid leukemic K562 cells. On the other hand, the differentiation agents DMSO and retinoic acid had no effect on DAB2 expression. Analysis of promoter activity with the human DAB2 luciferase reporter constructs suggested that the regulation is partially at the transcriptional level. The responsive sequences located within an 80-bp DAB2 promoter region. To determine the involvement of MEK1-p42/p44 MAPK pathway in mediating DAB2 gene expression, we have performed the following experiments and found that (i) there was sustained activation of p42/p44 MAPK, but not p38 MAPK, upon K562 cells differentiation; (ii) application of MEK1 inhibitor U0126 reduced the expression of DAB2 protein, mRNA and promoter activity, as well as cell differentiation; (iii) constitutively active MEK1 increased DAB2 promoter activity; and (iv) dominant negative ERK2 abolished constitutively active MEK1-induced DAB2 promoter activity. Taken together, our results indicate that DAB2 gene is induced upon megakaryocyte differentiation by the MEK1-p42/p44 MAPK pathway and may define a new role of DAB2 in hematopoietic cell differentiation.

Disabled-1 acts downstream of Reelin in a signaling pathway that controls laminar organization in the mammalian brain

Mutation of either reelin (Reln) or disabled-1 (Dab1) results in widespread abnormalities in laminar structures throughout the brain and ataxia in reeler and scrambler mice. Both exhibit the same neuroanatomical defects, including cerebellar hypoplasia with Purkinje cell ectopia and disruption of neuronal layers in the cerebral cortex and hippocampus. Despite these phenotypic similarities, Reln and Dab1 have distinct molecular properties. Reln is a large extracellular protein secreted by Cajal-Retzius cells in the forebrain and by granule neurons in the cerebellum. In contrast, Dab1 is a cytoplasmic protein which has properties of an adapter protein that functions in phosphorylation-dependent intracellular signal transduction. Here, we show that Dab1 participates in the same developmental process as Reln. In scrambler mice, neuronal precursors are unable to invade the preplate of the cerebral cortex and consequently, they do not align within the cortical plate. During development, cells expressing Dab1 are located next to those secreting Reln at critical stages of formation of the cerebral cortex, cerebellum and hippocampus, before the first abnormalities in cell position become apparent in either reeler or scrambler. In reeler, the major populations of displaced neurons contain elevated levels of Dab1 protein, although they express normal levels of Dab1 mRNA. This suggests that Dab1 accumulates in the absence of a Reln-evoked signal. Taken together, these results indicate that Dab1 functions downstream of Reln in a signaling pathway that controls cell positioning in the developing brain.