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61.
62.
A nearly universal feature of intron sequences is that even closely related
species exhibit a large number of insertion/deletion differences. The goal
of the analysis described here is to test whether the observed pattern of
insertion/deletion events in the genealogy of the myosin alkali light chain
(Mlc1) gene is consistent with neutrality, and if not, to determine the
underlying forces of evolutionary change. Mlc1 pre-mRNA is alternatively
spliced, and one constraint is that signals necessary for
tissue-specificity of directed splicing must be conserved. If the total
length of an intron is functionally constrained, then the distribution of
indels on branches of the gene genealogy should reflect a departure from
randomness. Here we perform a phylogenetic analysis, inferring ancestral
states wherever possible on a phylogeny of 29 alleles of Mlc1 from six
species of Drosophila. Observed patterns of indels on the genealogy were
compared to those from simulated data, with the result that we cannot
reject the null hypothesis of neutrality. A clear departure from a neutral
prediction was seen in the excess folding free energy predicted for the
introns flanking the alternatively spliced exon. Relative rate tests also
suggest a retardation in the rate of Mlc1 sequence evolution in the
simulans clade.
相似文献
63.
C Collin A G Papageorge M Sakakibara P L Huddie D R Lowy D L Alkon 《Biophysical journal》1990,58(3):785-790
Two electrode voltage clamp conditions were used to study the early effects on ionic membrane channels of the intracellularly injected proto-oncogenic form of c-Ha-ras (c-ras) and its oncogenic counterpart v-Ha-ras (v-ras). These experiments were conducted on isolated somata of identified fully differentiated neurons of the sea snail Hermissenda. 20 min after c-ras, and 10 min after v-ras intracellular injections into type B medial photoreceptors of Hermissenda, the peak amplitude of two outward potassium currents (IA and IC), across the isolated Type B soma membrane begin to decrease. These two currents have been previously isolated by differences in activation and inactivation kinetics and their response to pharmacological blockers. c- or v-ras injections did not have any effect on a voltage-dependent inward calcium current. Reduction of IA preceded that of IC. Current reductions due to c-ras, but not to v-ras injection reversed spontaneously after 40 min. The voltage dependence of the steady state inactivation of IA shifted toward more negative potentials with ras injections. Ras-mediated cell transformations therefore, could involve, perhaps as initial events, prolonged modification of membrane currents. 相似文献
64.
N Terminus of Sos1 Ras Exchange Factor: Critical Roles for the Dbl and Pleckstrin Homology Domains 总被引:9,自引:5,他引:4
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Xiaolan Qian William C. Vass Alex G. Papageorge Pieter H. Anborgh Douglas R. Lowy 《Molecular and cellular biology》1998,18(2):771-778
We have studied the functional importance of the N terminus of mouse Sos1 (mSos1), a ubiquitously expressed Ras-specific guanine nucleotide exchange factor whose C-terminal sequences bind Grb-2. Consistent with previous reports, addition of a myristoylation signal to mSos1 (MyrSos1) rendered it transforming for NIH 3T3 cells and deletion of the mSos C terminus (MyrSos1-ΔC) did not interfere with this activity. However, an N-terminally deleted myristoylated mSos1 protein (MyrSos1-ΔN) was transformation defective, although the protein was stable and localized to the membrane. Site-directed mutagenesis was used to examine the role of the Dbl and pleckstrin homology (PH) domains located in the N terminus. When mutations in the PH domain were introduced into two conserved amino acids either singly or together in MyrSos1 or MyrSos1-ΔC, the transforming activity was severely impaired. An analogous reduction in biological activity was seen when a cluster of point mutations was engineered into the Dbl domain. The mitogen-activation protein (MAP) kinase activities induced by the various Dbl and PH mutants of MyrSos1 correlated with their biological activities. When NIH 3T3 cells were transfected with a myristoylated Sos N terminus, their growth response to epidermal growth factor (EGF), platelet-derived growth factor, lysophosphatidic acid or serum was greatly impaired. The dominant inhibitory biological activity of the N terminus correlated with its ability to impair EGF-dependent activation of GTP-Ras and of MAP kinase, as well with the ability of endogenous Sos to form a stable complex with activated EGF receptors. The N terminus with mutations in the Dbl and PH domains was much less inhibitory in these biological and biochemical assays. In contrast to wild-type Sos1, nonmyristoylated versions of Sos1-ΔN and Sos1-ΔC did not form a stable complex with activated EGF receptors. We conclude that the Dbl and PH domains are critical for Sos function and that stable association of Sos with activated EGF receptors requires both the Sos N and C termini. 相似文献
65.
Conservation of alternative splicing and genomic organization of the myosin alkali light-chain (Mlc1) gene among Drosophila species 总被引:3,自引:0,他引:3
The Mlc1 gene of Drosophila melanogaster encodes two MLC1 isoforms via
developmentally regulated alternative pre-mRNA splicing. In larval muscle
and tubular and abdominal muscles of adults, all of the six exons are
included in the spliced mRNA, whereas, in the fibrillar indirect flight
muscle of adult, exon 5 is excluded from the mRNA. We show that this
tissue-specific pattern of alternative splicing of the Mlc1 pre-mRNA is
conserved in D. simulans, D. pseudoobscura, and D. virilis. Isolation and
sequencing of the Mlc1 genes from these three other Drosophila species have
revealed that the overall organization of the genes is identical and that
the genes have maintained a very high level of sequence identity within the
coding region. Pairwise amino acid identities are 94%-99%, and there are no
charge changes among the proteins. Total nucleotide divergence within the
coding region of the four genes supports the accepted genealogy of these
species, but the data indicate a significantly higher rate of amino acid
replacement in the branch leading to D. pseudoobscura. A comparison of
nucleotide substitutions in the coding portions of exon 5 and exon 6, which
encode the alternative carboxyl termini of the two MLC1 isoforms, suggests
that exon 5 is subject to greater evolutionary constraints than is exon 6.
In addition to the coding sequences, there is significant sequence
conservation within the 5' and 3' noncoding DNA and two of the introns,
including one that flanks exon 5. These regions are candidates for cis-
regulatory elements. Our results suggest that evolutionary constraints are
acting on both the coding and noncoding sequences of the Mlc1 gene to
maintain proper expression and function of the two MLC1 polypeptides.
相似文献
66.
67.
IL-7 is known foremost for its immunostimulatory capacities, including potent T cell-dependent catabolic effects on bone. In joint diseases like rheumatoid arthritis and osteoarthritis, IL-7, via immune activation, can induce joint destruction. Now it has been demonstrated that increased IL-7 levels are produced by human articular chondrocytes of older individuals and osteoarthritis patients. IL-7 stimulates production of proteases by IL-7 receptor-expressing chondrocytes and enhances cartilage matrix degradation. This indicates that IL-7, indirectly via immune activation, but also by a direct action on cartilage, contributes to joint destruction in rheumatic diseases. 相似文献
68.
Brajendra K. Tripathi Xiaolan Qian Philipp Mertins Dunrui Wang Alex G. Papageorge Steven A. Carr Douglas R. Lowy 《The Journal of cell biology》2014,207(5):627-642
DLC1 is a tumor suppressor protein whose full activity depends on its presence at focal adhesions, its Rho–GTPase activating protein (Rho-GAP) function, and its ability to bind several ligands, including tensin and talin. However, the mechanisms that regulate and coordinate these activities remain poorly understood. Here we identify CDK5, a predominantly cytoplasmic serine/threonine kinase, as an important regulator of DLC1 functions. The CDK5 kinase phosphorylates four serines in DLC1 located N-terminal to the Rho-GAP domain. When not phosphorylated, this N-terminal region functions as an autoinhibitory domain that places DLC1 in a closed, inactive conformation by efficiently binding to the Rho-GAP domain. CDK5 phosphorylation reduces this binding and orchestrates the coordinate activation DLC1, including its localization to focal adhesions, its Rho-GAP activity, and its ability to bind tensin and talin. In cancer, these anti-oncogenic effects of CDK5 can provide selective pressure for the down-regulation of DLC1, which occurs frequently in tumors, and can contribute to the pro-oncogenic activity of CDK5 in lung adenocarcinoma. 相似文献
69.
Adelmo L Cechin Marialva Sinigaglia Ney Lemke Sérgio Echeverrigaray Odalys G Cabrera Gonçalo AG Pereira José CM Mombach 《BMC plant biology》2008,8(1):50
Background
NEP1-like proteins (NLPs) are a novel family of microbial elicitors of plant necrosis. Some NLPs induce a hypersensitive-like response in dicot plants though the basis for this response remains unclear. In addition, the spatial structure and the role of these highly conserved proteins are not known. 相似文献70.
B M Willumsen A G Papageorge H F Kung E Bekesi T Robins M Johnsen W C Vass D R Lowy 《Molecular and cellular biology》1986,6(7):2646-2654
We used linker insertion-deletion mutagenesis to study the catalytic domain of the Harvey murine sarcoma virus v-rasH transforming protein, which is closely related to the cellular rasH protein. The mutants displayed a wide range of in vitro biological activity, from those that induced focal transformation of NIH 3T3 cells with approximately the same efficiency as the wild-type v-rasH gene to those that failed to induce any detectable morphologic changes. Correlation of transforming activity with the location of the mutations enabled us to identify three nonoverlapping segments within the catalytic domain that were dispensable for transformation and six other segments that were required for transformation. Segments that were necessary for guanosine nucleotide (GDP) binding corresponded to three of the segments that were essential for transformation; two of the three segments share strong sequence homology with other purine nucleotide-binding proteins. Loss of GDP binding was associated with apparent instability of the protein. Lesions in two of the three other required regions significantly reduced GDP binding, while small lesions in the last required region did not impair GDP binding or membrane localization. We speculate that this latter region interacts with the putative cellular target of ras. The results suggest that transforming ras proteins require membrane localization, guanosine nucleotide binding, and an additional undefined function that may represent interaction with their target. 相似文献