Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The antineoplastic drug estramustine is an adduct of estradiol and nor-nitrogen mustard. It has been shown that this drug interferes with microtubule assembly, an effect mediated by estramustine interaction with microtubule-associated proteins (MAPs). In the present report we demonstrate that estramustine and the phosphorylated derivative of the drug, estramustine-phosphate, inhibit the secretion of interleukin-3 by WEHI-3B cells. These studies also show that the estramustine derivative specifically interacts with a MAPs component found in these cells, which exhibited characteristics ressembling those of tau protein isoforms. Western blots using a unique monoclonal antibody MTB6.22 that recognizes microtubule-binding domains on MAPs, indicated that this WEHI protein factor contained the antigenic determinant that are functionally significant for microtubule assembly. ELISA assays using this antibody, also showed a decrease in the levels of the immunoreactive protein in WEHI cells after treatment with EMP. Interestingly, it has been recently described that the action of estramustine-phosphate is mediated by a direct interaction with MAP-binding sites on the microtubule surface, which are recognized by the site-specific monoclonal antibody. These findings together with immuno-precipitation experiments using anti-interleukin-3 antibodies and the inhibitory effect of the estramustine derivative on WEHI secretion process suggest that this anti-mitotic agent may block IL-3 secretion by a mechanism involving its interaction with a 'tau-like' MAPs component present in these cells.
Mol Cell Biochem 1992 Nov 18
PMID:The antineoplastic agent estramustine and the derivative estramustine-phosphate inhibit secretion of interleukin-3 in leukemic cells. Possible roles of MAPs. 148 50

The microtubule-associated protein Tau, a major component of brain microtubules, shares common repeated C-terminal sequences with the high molecular-weight protein MAP-2. It has been shown that tau peptides V187-G204 and V218-G235, representing two main repeats, induced brain tubulin assembly in a concentration-dependent fashion. The specific roles of these repeats in the interaction of tau with microtubules, and its antigenic nature were investigated using synthetic tau peptides and site-directed monoclonal antibodies. Tau peptides appeared to compete with MAP-2 incorporation into assembled microtubules. The interactions of the tau fragments with beta-tubulin peptides bearing the tau binding domain on tubulin were analyzed by fluorescence spectroscopy. The specificity of the binding was further demonstrated by the reactivity of tau and the tau peptides with a monoclonal anti-idiotypic antibody produced after immunization with the beta-II(422-434) tubulin peptide, as assessed by enzyme-linked immunoassay. Western blots confirmed the interaction of tau with the monoclonal antibody. In addition, immunoassays revealed a competition between the MAP-reacting monoclonal antibody and the tubulin peptide beta-II(422-434) for their interaction with the tau molecule.
Mol Cell Biochem 1992 May 13
PMID:Specific macromolecular interactions between tau and the microtubule system. 151 37

To define at the molecular biological level the effects of thyroid hormone on brain development we have examined cDNA clones of brain mRNAs and identified several whose expression is altered in hypothyroid animals during the neonatal period. Clones were identified with probes prepared by subtractive or differential hybridization, and those corresponding to mRNAs altered in hypothyroidism were further studied by Northern blot analysis. Using RNA prepared from whole brains, no effect of hypothyroidism was found on the expression of the astroglial gene coding for glial fibrillary acidic protein. Among genes of neuronal expression, no significant alterations were found in the steady state levels of mRNAs coding for neuron-specific enolase, microtubule-associated protein-2, Tau, or nerve growth factor. N-CAM mRNA increased slightly in hypothyroid brains. In contrast a 2- to 3-fold decrease was found in the mRNA coding for a novel neuronal gene, RC3. This is the first neuronal gene known to be significantly altered at the mRNA level by thyroid hormone deprivation. The abundance of the mRNAs for the major myelin proteins proteolipid protein, myelin basic protein, and myelin-associated glycoprotein, expressed by oligodendrocytes, were also decreased in hypothyroid brains. Developmental studies on RC3 and myelin-associated glycoprotein expression indicated that the corresponding mRNAs accumulate in the brain of normal rats during the first 15-20 days of neonatal life. A similar accumulation occurred in hypothyroid brains, but at much reduced levels. The results demonstrate that thyroid hormone controls the steady state levels of particular mRNAs during brain development.
Mol Endocrinol 1991 Feb
PMID:Effects of neonatal hypothyroidism on rat brain gene expression. 171 32

We have examined the time course of protein tyrosine phosphorylation in the meiotic cell cycles of Xenopus laevis oocytes and the mitotic cell cycles of Xenopus eggs. We have identified two proteins that undergo marked changes in tyrosine phosphorylation during these processes: a 42-kDa protein related to mitogen-activated protein kinase or microtubule-associated protein-2 kinase (MAP kinase) and a 34-kDa protein identical or related to p34cdc2. p42 undergoes an abrupt increase in its tyrosine phosphorylation at the onset of meiosis 1 and remains tyrosine phosphorylated until 30 min after fertilization, at which point it is dephosphorylated. p42 also becomes tyrosine phosphorylated after microinjection of oocytes with partially purified M-phase-promoting factor, even in the presence of cycloheximide. These findings suggest that MAP kinase, previously implicated in the early responses of somatic cells to mitogens, is also activated at the onset of meiotic M phase and that MAP kinase can become tyrosine phosphorylated downstream from M-phase-promoting factor activation. We have also found that p34 goes through a cycle of tyrosine phosphorylation and dephosphorylation prior to meiosis 1 and mitosis 1 but is not detectable as a phosphotyrosyl protein during the 2nd through 12th mitotic cell cycles. It may be that the delay between assembly and activation of the cyclin-p34cdc2 complex that p34cdc2 tyrosine phosphorylation provides is not needed in cell cycles that lack G2 phases. Finally, an unidentified protein or group of proteins migrating at 100 to 116 kDa increase in tyrosine phosphorylation throughout maturation, are dephosphorylated or degraded within 10 min of fertilization, and appear to cycle between low-molecular-weight forms and high-molecular-weight forms during early embryogenesis.
Mol Cell Biol 1991 Apr
PMID:Cell cycle tyrosine phosphorylation of p34cdc2 and a microtubule-associated protein kinase homolog in Xenopus oocytes and eggs. 200 92

Many of the human neurodegenerative conditions involve a reorganization of the neuronal cytoskeleton. The way in which the cytoskeleton is reorganized may provide a clue to the nature of the insult causing the neurodegeneration. The most common of these conditions is Alzheimer's disease, in which microtubules are lost from neurites that fill up with filamentous structures. One component of the filamentous structures is the microtubule-associated protein (MAP), tau. The tau protein is the product of a single gene expressed predominantly in neurons. The tau gene undergoes complex alternative splicing that is regulated both by development, and by the particular neuronal cell population in which it is expressed. Tau protein can be further modified, following its translation by phosphorylation at several sites. Much of the recent interest in the transition of tau to an abnormal state within a tangle-bearing neuron has focused on phosphorylation. A group of proteins that migrate slightly more slowly than tau, designated PHF-tau, are found in regions of the Alzheimer brain rich in dystrophic neurites, are hyperphosphorylated, fail to bind to microtubules, have distinct solubility properties, and can be derived from fractions of paired helical filaments (PHF).
Mol Neurobiol
PMID:Tau protein and neurodegeneration. 213 93

We have examined the relationship of the ubiquitous 68-70-kDa cytoskeletal-associated protein beta-internexin (Napolitano, E. W., Pachter, J. S., Chin, S. S. M., and Liem, R. K. H. (1985) J. Cell Biol. 101, 1323-1331) to heat-shock cognate 70 (hsc70), the major constitutive member of the mammalian heat-shock protein 70 (hsp70) family of stress proteins. We purify beta-internexin from rat brain microtubules and confirm its identity with hsc70 and the clathrin-uncoating ATPase by the following criteria: 1) The partial sequence of a cyanogen bromide-derived peptide from beta-internexin matches the inferred amino acid sequence of the cDNA clone pRC62 encoding hsc70 from rat brain (O'Malley, K., Mauron, A., Barchas, J. D., and Kedes, L. (1985) Mol. Cell. Biol. 5, 3476-3483). 2) Mixing experiments followed by two-dimensional gel analyses reveal the precise co-migration of beta-internexin, the clathrin-uncoating ATPase, and the in vitro translation product of cDNA clone pHSP-4 encoding rat brain hsc70. 3) beta-Internexin is recognized by a monoclonal antibody reactive against the class of hsp70 proteins. 4) beta-Internexin purified from a microtubule-associated protein-enriched fraction of rat brain by virtue of high affinity binding to ATP-agarose possesses clathrin cage-specific ATPase activity.
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PMID:Beta-internexin is a microtubule-associated protein identical to the 70-kDa heat-shock cognate protein and the clathrin uncoating ATPase. 252 48

1. Microtubules prepared from pig brain by two cycles of assembly-disassembly comprise cyclic nucleotide-independent protein kinase activity with phosvitin and troponin T as substrates. 2. Phosphocellulose chromatography resolved two phosvitin kinase activity peaks, one of which coincided with the troponin T kinase peak. 3. The activity peak corresponding to troponin T kinase was inhibited by heparin (I50 = 0.06 micrograms/ml), whereas the other phosvitin kinase peak was unaffected. 4. Both kinase fractions phosphorylated tubulin and microtubule-associated protein (MAP-2). 5. It is concluded that pig brain microtubules contain bound casein kinases I and II. The association may target the action of these kinases toward microtubular proteins in vivo.
Cell Mol Neurobiol 1988 Sep
PMID:Casein kinases I and II bound to pig brain microtubules. 322 59

Zinc-induced tubulin sheets were grown at pH values of 5.7 and 6.4 from porcine brain tubulin purified by phosphocellulose chromatography as well as from microtubule protein containing tubulin plus 20% (w/w) unfractionated microtubule-associated proteins (MAPs). Electron micrographs of negatively stained sheets were analyzed by a combination of real space cross-correlation and Fourier space methods, providing two-dimensional reconstructions to approximately 16 A resolution. The reconstructed images revealed that the protofilaments comprising zinc-induced sheets are composed of two clearly distinguishable alternating subunits, presumably corresponding to the alpha- and beta-tubulin monomers, whose morphologies are not significantly influenced by pH or the presence of MAPs during sheet assembly. Sheets assembled at pH 5.7, either with or without MAPs, were divided into two domains by a protofilament discontinuity which was not present in sheets assembled at pH 6.4, and displayed a 2.4 A reduction of the interprotofilament distance in projection relative to sheets assembled at pH 6.4. We conclude that morphological differences between tubulin subunits represent intrinsic structural features not contributed by MAPs, and that pH is more important than MAP content in influencing the lattice parameters of zinc-induced sheets.
J Ultrastruct Mol Struct Res 1988 Jan
PMID:Conservation of tubulin alpha-beta differences in zinc-induced sheets with variations in pH and microtubule-associated protein content. 335 54

A 13C nuclear magnetic resonance study of bovine microtubule protein was carried out at 43 kG in the presence and absence of colchicine 13C labeled at the tropolone methoxy. Analysis indicated that tubulin has at least two colchicine binding sites: a quasi-irreversibly bound, high-affinity site (i.e., the KD less than 5 microM site generally accepted as the site of colchicine action) as well as a low-affinity site(s) (KD approximately 650 microM) with which free colchicine rapidly exchanges (greater than 100 s-1). The methoxy resonance is broadened to different apparent extents as a result of binding at these two sites (50- vs. 150-Hz broadening for the high- and low-affinity sites, respectively) but undergoes no change in chemical shift upon binding. The low-affinity sites are interpreted to be analogous to the sites deduced by Schmitt and Atlas [Schmitt, H., & Atlas, D. (1976) J. Mol. Biol. 102, 743-758] from labeling studies using bromocolchicine. These sites are likely to be the sites responsible for the abrupt halt in microtubule assembly ("capping") observed at high colchicine concentrations (greater than 20 microM)--a qualitatively different behavior from that observed at low colchicine concentrations [Sternlicht, H., Ringel, I., & Szasz, J. (1983) Biophys. J. 42, 255-267]. Carbon-13 spectra from the aliphatic carbons of microtubule protein consists of narrow resonances--many with line widths less than 30 Hz--superimposed on a broad background. The narrow resonances were assigned to flexible regions in nontubulin proteins [microtubule-associated proteins (MAPs)], in accord with an earlier 1H nuclear magnetic resonance study of microtubule protein [Woody, R. W., Clark, D. C., Roberts, G. C. K., Martin, S. R., & Bayley, P. M. (1983) Biochemistry 22, 2186-2192]. This assignment was supported by 13C NMR analysis of phosphocellulose-purified (MAP-depleted) tubulin as well as heat-stable MAPs. Aliphatic carbons in the MAP preparations were characterized by narrow resonances indicative of carbons with considerable motional freedom whereas the aliphatic regions of phosphocellulose-purified tubulin were, for the most part, characterized by broad resonances indicative of carbons with restricted mobility. However, a moderately narrow resonance (approximately less than 50-Hz line width) coincident with the C gamma resonance of glutamate was detected in 13C NMR spectra of tubulin which indicated that a fraction of the glutamic acid residues is relatively mobile.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Carbon-13 nuclear magnetic resonance study of microtubule protein: evidence for a second colchicine site involved in the inhibition of microtubule assembly. 615 Jul 26

Zinc-induced tubulin sheets without microtubule-associated proteins (MAPs) were assembled from tubulin purified by phosphocellulose chromatography. Large, open sheets were obtained in five-minute incubations at pH 5.7. Electron micrographs of negatively stained sheets showed a protofilament arrangement similar to that observed for zinc-induced sheets with MAPs but with altered lattice parameters. The spacings measured from optical diffraction patterns demonstrated that the protofilaments were 2.2 A closer together in the sheets without MAPs. Each MAP-free sheet was also divided roughly in half by a discontinuity which was parallel to the protofilaments and the relationship between the two domains was deduced from computed transforms. Two-dimensional image processing was carried out by conventional Fourier techniques and by correlation analysis. The correlation analysis improved the reconstructions in this application, with the resolution limited by the inherent properties of the negative stain method to about 14 A. A prominent feature of the computed reconstructions was an alternation of light and dark protofilaments due to differential staining, as revealed by a study of folded sheets. Neighboring protofilaments are related by a 2-fold screw axis, as they are in zinc-induced sheets with MAPs, but the symmetry is masked by the differential staining. The major effect of MAP removal on the structure of the sheets is that the bilobed structure of alternate tubulin subunits is no longer observed. This observation and the closer spacing of protofilaments is consistent with the postulate that some of the MAP molecules lie in the groove between protofilaments and bind to several tubulin dimers.
J Mol Biol 1983 May 15
PMID:Structural changes in tubulin sheets upon removal of microtubule-associated proteins. 685 40


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