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Query: UNIPROT:P06889 (Mol)
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The genetic defect underlying Huntington's disease (HD) has been mapped to 4p16.3. Refined localization using recombinant HD chromosome analysis and allelic association analyses have identified two distinct candidate regions. Using a cDNA hybrid selection procedure we have cloned the gene for alpha-adducin, a subunit of a cytoskeletal protein crucial for spectrin-actin membrane plasticity. This gene maps to the proximal 2.2 Mb candidate region within 20 kb of D4S95. Alleles of markers at this locus have been shown to exhibit significant linkage disequilibrium with HD. A 4 kb alpha-adducin transcript was identified which is abundantly expressed in the caudate nucleus, the site of major neuronal loss in HD. Sequencing of the brain alpha-adducin cDNA from two HD patients and an age-matched control did not detect any sequence alterations specific to HD. However, we identified in brain cDNA of both patients and control samples, two alternately spliced brain exons, not previously described in the erythrocyte cDNA. A 93 bp exon is inserted in frame between codon 471 and 472 while a 34 bp exon inserted within codon 621 disrupts the frame and introduces a stop codon after 11 novel amino acids. The mapping of the adducin gene adjacent to D4S95 and its pattern of expression, as well as its potential for distinct alternately spliced variants, reinforces the necessity to accurately assess the role of the expression of this gene in the pathogenesis of HD.
Hum Mol Genet 1992 Dec
PMID:Cloning and mapping of the alpha-adducin gene close to D4S95 and assessment of its relationship to Huntington disease. 128 92

Injury to the axons of facial motoneurons stimulates increases in the synthesis of actin, tubulins, and GAP-43, and decreases in the synthesis of neurofilament proteins: mRNA levels change correspondingly. In contrast to this robust response of peripheral neurons to axotomy, injured central nervous system neurons show either an attenuated response that is subsequently aborted (rubrospinal neurons) or overall decreases in cytoskeletal protein mRNA expression (corticospinal and retinal ganglion neurons). There is evidence that these changes in synthesis are regulated by a variety of factors, including loss of endoneurially or target-derived trophic factors, positive signals arising from the site of injury, changes in the intraaxonal turnover of proteins, and substitution of target-derived trophic support by factors produced by glial cells. It is concluded that there is, as yet, no coherent explanation for the upregulation or downregulation of any of the cytoskeletal proteins following axotomy or during regeneration. In considering the relevance of these changes in cytoskeletal protein synthesis to regeneration, it is emphasized that they are unlikely to be involved in the initial outgrowth of the injured axons, both because transit times between cell body and injury site are too long, and because sprouting can occur in isolated axons. Injury-induced acceleration of the axonal transport of tubulin and actin in the proximal axon is likely to be more important in providing the cytoskeletal protein required for initial axonal outgrowth. Subsequently, the increased synthesis and transport velocity for actin and tubulin increase the delivery of these proteins to support the increased volume of the maturing regenerating axons. Reduction in neurofilament synthesis and changes in neurofilament phosphorylation may permit the increased transport velocity of the other cytoskeletal proteins. There is little direct evidence that alterations in cytoskeletal protein synthesis are necessary for successful regeneration, nor are they sufficient in the absence of a supportive environment. Nevertheless, the correlation that exists between a robust cell body response and successful regeneration suggests that an understanding of the regulation of cytoskeletal protein synthesis following axon injury must be a part of any successful strategy to improve the regenerative capacity of the central nervous system.
Mol Neurobiol
PMID:Changes in cytoskeletal protein synthesis following axon injury and during axon regeneration. 147 74

Axonal transport is known to be impaired in peripheral nerve of experimentally diabetic rats. As axonal transport is dependent on the integrity of the neuronal cytoskeleton, we have studied the way in which rat brain and nerve cytoskeletal proteins are altered in experimental diabetes. Rats were made diabetic by injection of streptozotocin (STZ). Up to six weeks later, sciatic nerves, spinal cords, and brains were removed and used to prepare neurofilaments, microtubules, and a crude preparation of cytoskeletal proteins. The extent of nonenzymatic glycation of brain microtubule proteins and peripheral nerve tubulin was assessed by incubation with 3H-sodium borohydride followed by separation on two-dimensional polyacrylamide gels and affinity chromatography of the separated proteins. There was no difference in the nonenzymatic glycation of brain microtubule proteins from two-week diabetic and nondiabetic rats. Nor was the assembly of microtubule proteins into microtubules affected by the diabetic state. On the other hand, there was a significant increase in nonenzymatic glycation of sciatic nerve tubulin after 2 weeks of diabetes. We also identified an altered electrophoretic mobility of brain actin from a cytoskeletal protein preparation from brain of 2 week and 6 week diabetic rats. An additional novel polypeptide was demonstrated with a slightly more acidic isoelectric point than actin that could be immunostained with anti-actin antibodies. The same polypeptide could be produced by incubation of purified actin with glucose in vitro, thus identifying it as a product of nonenzymatic glycation. These results are discussed in relation to data from a clinical study of diabetic patients in which we identified increased glycation of platelet actin. STZ-diabetes also led to an increase in the phosphorylation of spinal cord neurofilament proteins in vivo during 6 weeks of diabetes. This hyperphosphorylation along with a reduced activity of a neurofilament-associated protein kinase led to a reduced incorporation of 32P into purified neurofilament proteins when they were incubated with 32P-ATP in vitro. Our combined data show a number of posttranslation modifications of neuronal cytoskeletal proteins that may contribute to the altered axonal transport and subsequent nerve dysfunction in experimental diabetes.
Mol Neurobiol
PMID:Posttranslational modifications of nerve cytoskeletal proteins in experimental diabetes. 147 75

In a recent paper we described a system in which glucocorticoid receptors associate with particulate complexes containing tubulin [Cancer Res. 49 (1989) 2222s-2229s]. When L cell cytosol is mixed with a microtubule stabilizing buffer and heated to 37 degrees C, the receptor becomes associated with a complex that can be centrifuged out of solution at 150,000 g. In this work we show that the glucocorticoid receptor-cytoskeletal protein complex forms in a temperature and glutamate-dependent manner. Molybdate does not affect generation of the cytoskeletal protein complex but it inhibits association of the receptor with the complex. This suggests that transformation of the receptor to its DNA-binding form is required for interaction with the cytoskeletal complex. Colchicine has no effect on generation of the particulate complex or on the association of receptor with it, suggesting that formation of the complex does not represent a classic in vitro process of tubulin polymerization.
J Steroid Biochem Mol Biol 1992 Mar
PMID:Association of the transformed glucocorticoid receptor with a cytoskeletal protein complex. 156 45

Different liver diseases are associated with modifications in hepatocyte cytoskeletal organization and formation of Mallory bodies (MBs). Since the structure of a protein is critical for its function, we studied the changes in the molecular structure of the cytoskeletal protein in the liver from mice fed griseofulvin (GF), which is a good animal model for studying liver disease. Using pressure-tuning infrared spectroscopy we compared the infrared spectra of the cytoskeletal proteins from control liver and griseofulvin treated liver. The results show that the overall structure of the cytoskeletal protein was modified by the griseofulvin treatment. A relative increase in the amount of alpha-helices to beta-sheets was observed in the liver cytoskeleton from the GF-treated mice. Moreover, the random coil and the turn segments were dramatically decreased compared to controls. Pressure-induced modifications including denaturation were irreversible in the control samples whereas they were reversible in the griseofulvin-treated samples. These changes reflect important fundamental modifications in the molecular structure of the cytoskeletal proteins in the griseofulvin-treated hepatocytes. We suggest that these changes are related to the modification of the organization of intermediate filaments and the formation of MBs that occur in the GF-treated liver.
Exp Mol Pathol 1991 Oct
PMID:Alteration in molecular structure of cytoskeleton proteins in griseofulvin-treated mouse liver: a pressure tuning infrared spectroscopy study. 193 12

Previous experiments with individual cell couples formed between cloned T helper (Th) cells and antigen-presenting cells have led us to suggest that the cytoskeletal protein talin may be associated with the cell surface protein LFA-1 in the Th cell. In order to examine this suggestion, we induced the surface capping of LFA-1 with suitable specific antibody reagents on the intact Th cells, and then determined by double immunofluorescence microscopic experiments, whether talin was co-clustered with the LFA-1 caps. With untreated Th cells, capping of LFA-1 did not result in any redistribution of intracellular talin. However, if the intact Th cells were treated with the phorbol ester PMA, the capping of LFA-1 resulted in a co-clustering of talin with the LFA-1 caps, but not a alpha-actinin. The capping of TCR or CD4 on the Th cells with or without pretreatment with PMA did not lead to any such co-clustering of talin with these caps. PMA treatment of the Th cells therefore induces a direct or indirect association of talin with LFA-1 underneath the Th cell surface. PMA treatment of the Th cells also increased their polarized spreading and adherence to substrata, as had been observed before. We found, furthermore, that this increased adherence upon PMA-treatment was inhibited by the presence of antibodies to LFA-1. The association of talin, and very likely also F-actin microfilaments, with LFA-1 appears to mediate a generalized increased adhesivity of the Th cells. The relevance of these findings with isolated Th cells to the interaction of Th cells with specific antigen-presenting cells is discussed.
J Mol Cell Immunol 1990
PMID:The PMA-induced specific association of LFA-1 and talin in intact cloned T helper cells. 215 Apr 84

Microtubule-associated protein 2 (MAP-2), a cytoskeletal protein of 280 kilodalton that is highly enriched in dendrites and neuronal perikarya, is subject to both cyclic AMP-, calcium/calmodulin-, and calcium/phospholipid-regulated phosphorylation when incubated with [gamma-32P]ATP in vitro. We have analyzed the different sites in MAP-2 phosphorylated by these three kinases in fresh or boiled cytosol from different regions of the rat brain, in particular the olfactory bulb, where only one form (MAP-2B) is present, and the cerebral cortex, where both forms (MAP-2A and MAP-2B) are equally enriched. Cyclic AMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II phosphorylated four common phosphorylation sites, as well as a number of distinct sites that were unique to each enzyme. Calcium/phospholipid-dependent protein kinase phosphorylated a minimum of 15 sites, only one of which appeared to be shared with the other protein kinases. Only serine residues were phosphorylated by cyclic AMP-dependent and calcium/phospholipid-dependent protein kinases, while both serine and threonine residues were phosphorylated by calcium/calmodulin-dependent protein kinase II. No differences were observed in the peptide maps of phospho-MAP-2 prepared from different brain regions. These results emphasize the complexity of the phosphorylation systems that may regulate the function of MAP-2 in situ.
J Mol Neurosci 1989
PMID:Multisite phosphorylation of microtubule-associated protein 2 (MAP-2) in rat brain: peptide mapping distinguishes between cyclic AMP-, calcium/calmodulin-, and calcium/phospholipid-regulated phosphorylation mechanisms. 256 75

The cytoskeletal protein talin was found to undergo enhanced phosphorylation at tyrosine residues in chicken embryo fibroblasts following transformation by Rous sarcoma virus. An increase in the tyrosine phosphorylation of talin was also observed within 6 h in cells infected by the temperature-sensitive mutant tsNY68 after a shift from the nonpermissive to the permissive temperature. The overall extent of phosphorylation was 0.07 mol of phosphate per mol of talin and was not appreciably altered by transformation. In uninfected cells talin was shown to be phosphorylated at multiple sites by tryptic peptide mapping. Following transformation most of these sites remained phosphorylated, to the same or to a lesser extent, while novel, phosphotyrosine-containing phosphopeptides appeared. Talin was phosphorylated at tyrosine in cells infected by Rous sarcoma virus mutants which induce altered or partial transformation morphologies; thus the increased phosphorylation of talin at tyrosine occurred irrespective of the morphology induced. Transformation by Y73 also induced elevated levels of phosphotyrosine in talin, whereas transformation by the avian erythroblastosis and Fujinami sarcoma viruses did not.
Mol Cell Biol 1987 Jan
PMID:Phosphorylation of talin at tyrosine in Rous sarcoma virus-transformed cells. 303 68

The Epstein-Barr virus (EBV) latent infection membrane protein (LMP) is likely to be an important mediator of EBV-induced cell proliferation, since it is one of the few proteins encoded by the virus in latent infection and since production of this protein in Rat-1 cells results in their conversion to a fully transformed phenotype. LMP was previously noted to localize to patches at the cell periphery. In this paper we examine the basis of LMP patching in EBV-infected, transformed lymphocytes. Our data indicate that LMP is associated with the cytoskeletal protein vimentin. Although LMP is fully soluble in isotonic Triton X-100 buffer, only 50% of it is extracted from cells in this solution. The rest remains bound to the cytoskeleton. LMP undergoes phosphorylation, and phosphorylated LMP is preferentially associated with the cytoskeleton. As judged by both immunofluorescence and immunoelectron microscopy, the vimentin network in EBV-transformed lymphocytes or EBV-infected Burkitt tumor lymphocytes is abnormal. Vimentin and LMP often colocalize in a single patch near the plasma membrane. In response to Colcemid treatment of EBV-infected cells, vimentin reorganizes into perinuclear rings, as it does in uninfected cells. LMP is associated with these perinuclear rings. Vimentin (or a vimentin-associated protein) may be a transducer of an LMP transmembrane effect in lymphoproliferation.
Mol Cell Biol 1987 Jul
PMID:An Epstein-Barr virus transforming protein associates with vimentin in lymphocytes. 303 44

Two different mutant human beta-actin genes have been introduced into normal diploid human (KD) fibroblasts and their immortalized derivative cell line, HuT-12, to assess the impact of an abnormal cytoskeletal protein on cellular phenotypes such as morphology, growth characteristics, and properties relating to the neoplastic phenotype. A mutant beta-actin containing a single mutation (Gly-244----Asp-244) was stable and was incorporated into cytoskeletal stress fibers. Transfected KD cells which expressed the stable mutant beta-actin in excess of normal beta-actin were morphologically altered. In contrast, a second mutant beta-actin gene containing two additional mutations (Gly-36----Glu-36 and Glu-83----Asp-83, as well as Gly-244----Asp-244) did not alter cell morphology when expressed at high levels in transfected cells, but the protein was labile and did not accumulate in stress fibers. In both KD and HuT-12 cells, endogenous beta- and gamma-actin decreased in response to high-level expression of the stable mutant beta-actin, in a manner consistent with autoregulatory feedback of actin concentrations. Since the percent decreases in the endogenous beta- and gamma-actins were equal, the ratio of net beta-actin (mutant plus normal) to gamma-actin was significantly increased in the transfected cells. Antisera capable of distinguishing the mutant from the normal epitope revealed that the mutant beta-actin accumulated in stress fibers but did not participate in the formation of the actin filament-rich perinuclear network. These observations suggest that different intracellular locations differentially incorporate actin into cytoskeletal microfilaments. The dramatic impact on cell morphology and on beta-actin/gamma-actin ratios in the transfected diploid KD cells may be related to the acquisition of some of the characteristics of cells that underwent the neoplastic transformation event that originally led to the appearance of the beta-actin mutations.
Mol Cell Biol 1987 Jul
PMID:Expression of transfected mutant beta-actin genes: alterations of cell morphology and evidence for autoregulation in actin pools. 361 98


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