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At least 343 records · Page 19Linked to original sources
PubMed2005

New end take off: regulating cell polarity during the fission yeast cell cycle.

Cell polarization is a major event of the cell cycle and underlies the function of most cells. Cell polarity is often achieved through the coordinated organization of the microtubule and act in cytoskeletons. Dramatic changes in cell polarization occur during the cell cycle and are subject to regulation by cell cycle controls. Cells of the fission yeast Schizosaccharomyces pombe grow by tip extension in a cell cycle-controlled manner. During G2 phase, these cells exhibit a transition in cell polarization known as New End Take Off (NETO), in which monopolar cells initiate bipolar growth. Dynamic microtubules contribute to this process by depositing at cell ends the microtubule plus end proteins tea1p and tea4p, which are necessary for NETO. We discuss here how these proteins may recruit for 3p, a formin responsible for actin nucleation, as well as two other actin binding proteins, bud6p and sla2p, to initiate cell polarization at the new end of the cell. Thus, the study of NETO is revealing a mechanism by which the plus ends of microtubules regulate the spatial organization of actin.

Actins↗
PubMed2005

WNT/PCP signaling pathway and human cancer (review).

WNT/planar cell polarity (PCP) signaling pathway controls tissue polarity and cell movement through the activation of RHOA, c-Jun N-terminal kinase (JNK), and nemo-like kinase (NLK) signaling cascades. PCP is induced in Drosophila by the asymmetrical localization of Frizzled-Dishevelled-Diego-Starry night (Flamingo) complex and Van Gogh (Strabismus)-Prickle complex. Here, WNT/PCP signaling pathway implicated in human carcinogenesis is reviewed. Human WNT5A, WNT5B, and WNT11 are representative non-canonical WNTs transducing PCP signals through FZD3 or FZD6 receptors, and ROR1, ROR2 or PTK7 co-receptors. Human VANGL1, VANGL2 (Van Gogh homologs), CELSR1, CELSR2, CELSR3 (Starry night homologs), DVL1, DVL2, DVL3 (Dishevelled homologs), PRICKLE1, PRICKLE2 (Prickle homologs), and ANKRD6 (Diego homolog) are core PCP signaling molecules. MAGI3 assembles FZD, VANGL, PTEN, and adhesion molecules. Dishevelled-dependent WNT/PCP signals are transduced to the RHOA signaling cascade through Formin homology proteins DAAM1 and DAAM2, and to the JNK signaling cascade through MAPKKKs and MAPKK4/7. Dishevelled-independent WNT/ PCP signals are transduced to the NLK signaling cascade through MAP3K7 (TAK1). ANKRD6, NKD1 and NKD2 induce class switch from the WNT/GSK3beta signaling pathway to the WNT/PCP signaling pathway. WNT5A is up-regulated in various types of human cancer, such as gastric cancer, lung cancer, and melanoma. FZD3/FZD6 receptor and ROR2 co-receptor transduce WNT5A signal in gastric cancer. Aberrant activation of WNT/PCP signaling pathway in human cancer leads to more malignant phenotypes, such as abnormal tissue polarity, invasion, and metastasis. cDNA-PCR, microarray or ELISA reflecting aberrant activation of WNT/PCP signaling pathway could be developed as novel cancer prognostics. Single nucleotide polymorphism (SNP) and copy number polymorphism (CNP) of WNT/PCP signaling molecules mentioned above are suitable for use in screening of cancer predisposition, especially for gastric cancer. Antibody, RNAi, or small molecule compounds to regulate the function of WNT/PCP signaling molecules mentioned above are good candidates for development as novel cancer therapeutics.

Animals↗
PubMed2005

The regulatory subunit of PDE6 interacts with PACSIN in photoreceptors.

PURPOSE: In photoreceptors, phosphodiesterase 6 (PDE6) is regulated in response to light, due to the shuttling of a regulatory subunit (PDE6gamma) between the catalytic subunits of PDE6 and the activated form of transducin. We showed previously that PDE6gamma is able to interact with the Src-homology type 3 (SH3) domain of formin-binding protein 17 (FBP17), a protein involved in membrane receptor endocytosis. FBP17 was not detected in rat retina. Therefore, we looked for other SH3 domain-containing proteins that might interact with PDE6gamma in rat photoreceptors. METHODS: Several SH3 domains highly homologous to this domain of FBP17 were found by structural alignment. Yeast two-hybrid system and GST pull-downs were used to test interaction of PDE6gamma with these putative partners. Expression patterns in rat retina of the SH3 containing candidates were also determined by immunohistochemistry and western blotting. GST pull-downs and co-immunopreciptations were then used to test in vivo interaction with PDE6gamma in rat retina extracts. Colocalization and light translocation of PDE6gamma and one of its partner were studied by confocal microscopy. RESULTS: PDE6gamma interacts in vitro with a number of SH3 domains. These interactions involve a polyprolin motif located between amino acids 20 and 28 of PDE6gamma. Several of the putative partners of PDE6gamma are expressed in photoreceptor cells and might therefore interact in vivo with PDE6gamma. Our results show that only PACSIN, a protein implicated in endocytosis, was found to interact with PDE6gamma in rat retina extracts. The colocalization of the two proteins occurs in photoreceptor inner segments and synapses and is greatly enhanced upon illumination of the retina. CONCLUSIONS: PDE6gamma function is mostly documented in the regulation of phototransduction. Our results provide evidence that in vitro PDE6gamma has a broad pattern of SH3 containing partners expressed in photoreceptors. PDE6gamma interaction with PACSIN points to a possible role of PDE6gamma in endocytosis. Further studies will be needed to understand the exact role of PDE6gamma-PACSIN interactions in photoreceptors. The description of this new function of PDE6gamma might help to understand the molecular mechanism of the severe retinal degeneration observed in PDE6gamma knock-out mice.

Animals↗
PubMed1996

Bni1p implicated in cytoskeletal control is a putative target of Rho1p small GTP binding protein in Saccharomyces cerevisiae.

The RHO1 gene encodes a homolog of mammalian RhoA small GTP binding protein in the yeast Saccharomyces cerevisiae. Rho1p is localized at the growth sites, including the bud tip and the cytokinesis site, and is required for bud formation. We have recently shown that Pkc1p, a yeast homolog of mammalian protein kinase C, and glucan synthase are targets of Rho1p. Using the two-hybrid screening system, we cloned a gene encoding a protein which interacted with the GTP-bound form of Rho1p. This gene was identified as BNI1, known to be implicated in cytokinesis or establishment of cell polarity in S.cerevisiae. Bni1p shares homologous domains (FH1 and FH2 domains) with proteins involved in cytokinesis or establishment of cell polarity, including formin of mouse, capu and dia of Drosophila and FigA of Aspergillus. A temperature-sensitive mutation in which the RHO1 gene was replaced by the mammalian RhoA gene showed a synthetically lethal interaction with the bni1 mutation and the RhoA bni1 mutant accumulated cells with a deficiency in cytokinesis. Furthermore, this synthetic lethality was caused by the incapability of RhoA to activate Pkc1p, but not glucan synthase. These results suggest that Rho1p regulates cytoskeletal reorganization at least through Bni1p and Pkc1p.

Base Sequence↗
PubMed1998

Further characterization of the DFNA1 audiovestibular phenotype.

BACKGROUND: Autosomal dominant, nonsyndromic, hereditary hearing impairment in a large Costa Rican kindred is caused by a mutation in the human homolog of the Drosophila diaphanous gene. OBJECTIVE: To further characterize the phenotype of DFNA1 with comprehensive audiovestibular evaluation and computed tomography of the temporal bone. PATIENTS: One affected child and 2 affected adults of the Costa Rican kindred who harbor a mutation in the diaphanous gene. SETTING: Medical Center at the University of California, San Francisco. INTERVENTION: Otologic and neuro-otologic examination; pure tone audiometry, speech audiometry, and immitance testing; auditory evoked potentials, electrocochleography, and otoacoustic emissions; electronystagmography and vestibular autorotation tests; and computed tomography of the temporal bone. RESULTS: The youngest subject, an 8-year-old boy, had a mild hearing loss, intact stapedial reflexes, otoacoustic emissions at high frequencies, normal auditory evoked potentials, and electrocochleographic findings consistent with endolymphatic hydrops. The two adults had severe to profound bilateral sensorineural hearing impairment. Electronystagmography disclosed normal vestibular function. Computed tomography demonstrated normal external, middle, and inner ear structures. CONCLUSIONS: These results suggest that the early low-frequency hearing loss in this family is associated with endolymphatic hydrops. Elucidation of the role of the diaphanous gene in hearing will therefore lead to a better understanding of the mechanism of endolymphatic hydrops.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Perturbation of RET signaling in the embryonic kidney.

We have used a RET-Ig fusion protein to disrupt signaling in the rat embryonic kidney development pathway. Treatment of embryonic kidney organ cultures with RET-Ig results in a decrease in branching of the ureteric bud and a down regulation in expression of the Wnt-11, Wnt-4, and ld genes. These data suggest that Wnt-11, Wnt-4, and ld function downstream of RET signaling in normal development. Expression of BMP-7, shh, and ptc were uneffected by RET-Ig treatment, implying that these genes are regulated independently of ret. We have also performed immunohistochemistry with a GFR alpha-1 specific polyclonal antisera to localize GFR alpha-1 protein expression in the developing kidney.

Animals↗
PubMed2024

Cytoskeletal mechanisms regulating attaching/effacing bacteria interactions with host cells: It takes a village to build the pedestal.

The actin cytoskeleton is a key cellular structure subverted by pathogens to infect and survive in or on host cells. Several pathogenic strains of Escherichia coli, such as enteropathogenic E. coli (EPEC) and enterohemorrhagic E. coli (EHEC), developed a unique mechanism to remodel the actin cytoskeleton that involves the assembly of actin filament-rich pedestals beneath the bacterial attachment sites. Actin pedestal assembly is driven by bacterial effectors injected into the host cells, and this structure is important for EPEC and EHEC colonization. While the interplay between bacterial effectors and the actin polymerization machinery of host cells is well-understood, how other mechanisms of actin filament remodelling regulate pedestal assembly and bacterial attachment are poorly investigated. This review discusses the gaps in our understanding of the complexity of the actin cytoskeletal remodelling during EPEC and EHEC infection. We describe possible roles of actin depolymerizing, crosslinking and motor proteins in pedestal dynamics, and bacterial interactions with the host cells. We also discuss the biological significance of pedestal assembly for bacterial infection.

Humans↗
PubMed2006

Rac/Rho pathway regulates actin depolymerization induced by aminoglycoside antibiotics.

Stress stimuli can lead to remodeling of the actin cytoskeleton and subsequent alteration of cell adhesion and permeation as well as cell functions and cell fate. We investigated redox-dependent Rho GTPase-linked pathways controlling the actin cytoskeleton in the inner ear of the CBA mouse, by using aminoglycoside antibiotics as a noxious stimulus that causes loss of sensory cells via the formation of reactive oxygen species. Kanamycin treatment in vivo interfered with the formation of F-actin, disturbed the arrangement of beta-actin in the stereocilia of outer hair cells, and altered the intermittent adherens junction/tight junction complexes between outer hair cells and supporting cells. The drug treatment also activated Rac1 and promoted the formation of the complex of Rac1 and p67phox while decreasing the activity of RhoA and reducing the formation of the RhoA/p140mDia complex. In inner-ear-derived cell lines, expression of mutated Rac1 changed the structural arrangement of F-actin and diminished the immunoreactivity of p140mDia. These findings suggest that actin depolymerization induced by kanamycin is mediated by Rac1 activation, followed by the formation of superoxide by NADPH oxidase. These changes will ultimately contribute to aminoglycoside-induced loss of hair cells.

Actins↗
PubMed1993

Physical mapping of DNA markers in the q13-q22 region of the human X chromosome.

DNA probe screening of somatic cell hybrids derived from females with X;autosome translocations has enabled us to define eight new breakpoints within the Xq13-q22 region. Together with other X-chromosome rearrangements that have been described earlier, these breakpoints subdivide the Xq21-q22 region into 20 intervals. Our panel refines the physical assignment of 40 probes in the Xq21-q22 segment. Thus, these X-chromosome rearrangements are useful tools for ordering X-linked markers and genes on the proximal long arm of the human X chromosome.

Amenorrhea↗
PubMed1997

Eleven X chromosome breakpoints associated with premature ovarian failure (POF) map to a 15-Mb YAC contig spanning Xq21.

Eleven balanced X-autosome translocations associated with premature ovarian failure (POF) were mapped to a YAC contig spanning most of Xq21 and constructed between the DXS223 and DXS1171 loci. The contig corresponds to a genomic region of about 15 Mb and contains the whole X-Y homologous region. The most proximal and most distal breakpoints associated with POF were mapped 15 Mb apart. The remaining breakpoints were localized along this large region, in the X-specific and in the X-Y homologous region. Four of the YACs contained two breakpoints in the same or in flanking STS intervals. Our results confirm the cytological findings and suggest that a minimum number of eight different genes in Xq21 may be involved with ovary development. Interruption of such loci could be the cause of POF.

Carrier Proteins↗
PubMed1997

An ancient conserved gene expressed in the human inner ear: identification, expression analysis, and chromosomal mapping of human and mouse antiquitin (ATQ1).

We constructed and screened a human fetal cochlear cDNA library to identify genes involved in hearing and deafness. From this library we isolated a cDNA corresponding to the highly conserved ancient gene antiquitin (ATQ1). The plant homolog of ATQ1 is thought to be involved in regulating turgor pressure, a function that also would be essential for cells of the mammalian cochlea. Northern blots of 13 human fetal tissues show antiquitin to be highly expressed in cochlea, ovary, eye, heart, and kidney. Using RT-PCR of rat cochlear hair cell-specific cDNA libraries, we detect antiquitin expression in outer hair cells, but not in inner or vestibular type 1 hair cells, suggesting that antiquitin is not expressed ubiquitously in the cochlea. Human ATQ1 was mapped to human chromosome region 5q31 using fluorescence in situ hybridization, and mouse ATQ1 was mapped to mouse chromosome 18 by single-strand conformation polymorphism mapping of interspecific backcross progeny DNAs. Four human antiquitin-like sequences, possibly pseudogenes, were also identified and mapped.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Evidence for tension-based regulation of Drosophila MAL and SRF during invasive cell migration.

Cells migrating through a tissue exert force via their cytoskeleton and are themselves subject to tension, but the effects of physical forces on cell behavior in vivo are poorly understood. Border cell migration during Drosophila oogenesis is a useful model for invasive cell movement. We report that this migration requires the activity of the transcriptional factor serum response factor (SRF) and its cofactor MAL-D and present evidence that nuclear accumulation of MAL-D is induced by cell stretching. Border cells that cannot migrate lack nuclear MAL-D but can accumulate it if they are pulled by other migrating cells. Like mammalian MAL, MAL-D also responds to activated Diaphanous, which affects actin dynamics. MAL-D/SRF activity is required to build a robust actin cytoskeleton in the migrating cells; mutant cells break apart when initiating migration. Thus, tension-induced MAL-D activity may provide a feedback mechanism for enhancing cytoskeletal strength during invasive migration.

Actin Cytoskeleton↗
PubMed2006

HAN11 binds mDia1 and controls GLI1 transcriptional activity.

BACKGROUND: The Hedgehog pathway is important in normal and diseased skin. One of the key transcription factors in the pathway is GLI1. GLI1-dependent transcription is positively regulated by DYRK1A, which is reported to bind HAN11. HAN11 is the human homologue of AN11, which controls flavonoid synthesis in plants. OBJECTIVE: We wanted to identify other binding partners of HAN11 and investigate whether HAN11 regulates GLI1-dependent transcription. METHODS: We used TAP-tag purification and GST pull down to identify protein-protein interactions and performed luciferase assays of transcriptional activity. We used immunofluorescence microscopy to examine the subcellular distribution of HAN11, mDia1 and GLI1. We performed in situ hybridisation to compare expression of HAN11 with GLI1 and patched in mouse embryos. RESULTS: We identified the cytoskeletal regulator mDia1 as a binding partner of HAN11. We showed that HAN11 binds the FH2 actin binding domain of mDia1 and confirmed that HAN11 also interacts with DYRK1A. Overexpression of mDia1 or active RhoA caused translocation of HAN11 from nucleus to cytoplasm. HAN11 and mDia1 repressed DYRK1A-dependent GLI1 transcriptional activity. HAN11 overexpression decreased SZ95 sebocyte proliferation and increased cytoplasmic GLI1. AN11 was highly expressed in E10.5 mouse embryo limb buds, in an overlapping pattern with Ptc and GLI1. CONCLUSION: These results suggest that AN11 may be a physiological regulator of GLI1 transcriptional activity.

Adaptor Proteins, Signal Transducing↗
PubMed2026

TTC19 and FMNL2 gene variants in a pediatric case of mitochondrial disorder with renal tubular acidosis.

Mitochondrial complex III deficiency caused by pathogenic variants in TTC19 is a heterogeneous disorder typically presenting with progressive neurological involvement in late childhood. Early-onset of disease with predominant renal manifestations are uncommon and may complicate diagnosis. We report a child presenting with developmental delay, failure to thrive, lactic acidosis, and distal renal tubular acidosis (dRTA), raising suspicion of an underlying mitochondrial disorder. Whole exome sequencing (WES) analysis identified a homozygous intron-exon boundary deletion of 31 bp (c.463-19_474del) in TTC19 predicted to disrupt splicing, with functional evidence demonstrating aberrant transcript formation, reduced gene expression, and mitochondrial dysfunction in patient-derived fibroblasts. Based on the biochemical findings, re-analysis of exome data revealed a novel homozygous canonical splice-site variant (c.783-1G>A) in FMNL2. The splicing assay showed the skipping of exon 9, and reduced expression in the fibroblasts. This case expands the clinical spectrum of TTC19-related mitochondrial complex III deficiency with early-onset renal tubular acidosis. While TTC19 is the most plausible primary disease-causing gene, the functional disruption of FMNL2 suggests a potential contributory role or association with the renal phenotype. Hence, these findings highlight the importance of genomic re-analysis along with functional studies in resolving complex multisystem disorders.

Female↗
PubMed2006

Organization and function of the actin cytoskeleton in developing root cells.

The actin cytoskeleton is a highly dynamic structure, which mediates various cellular functions in large part through accessory proteins that tilt the balance between monomeric G-actin and filamentous actin (F-actin) or by facilitating interactions between actin and the plasma membrane, microtubules, and other organelles. Roots have become an attractive model to study actin in plant development because of their simple anatomy and accessibility of some root cell types such as root hairs for microscopic analyses. Roots also exhibit a remarkable developmental plasticity and possess a delicate sensory system that is easily manipulated, so that one can design experiments addressing a range of important biological questions. Many facets of root development can be regulated by the diverse actin network found in the various root developmental regions. Various molecules impinge on this actin scaffold to define how a particular root cell type grows or responds to a specific environmental signal. Although advances in genomics are leading the way toward elucidating actin function in roots, more significant strides will be realized when such tools are combined with improved methodologies for accurately depicting how actin is organized in plant cells.

Actin Depolymerizing Factors↗
PubMed2006

Measurement of activity of rho GTPases during mitosis.

The members of Rho-family GTPases regulate progression through mitosis. Rho induces the contractile ring at the equatorial cortex of the dividing cell, and thus works as a molecular switch between nuclear division and cytokinesis. Cdc42 regulates the progression from prometaphase to metaphase by stabilizing microtubule attachment to the kinetochore. These results suggest that Rho GTPases are activated at specific points in mitosis and regulate each step. Here we describe the methods to analyze the activity and regulation of Rho GTPases during mitosis.

Carrier Proteins↗