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Multisite RNA binding and release of polypyrimidine tract binding protein during the regulation of c-src neural-specific splicing

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MOLECULAR CELL 2000年第6期5卷 949-957页

作者： Chou, MY Underwood, JG Nikolic, J Luu, MHT Black, DL Univ Calif Los Angeles Howard Hughes Med Inst Los Angeles CA 90095 USA Univ Calif Los Angeles Inst Mol Biol Los Angeles CA 90095 USA Univ Calif Los Angeles Dept Microbiol & Mol Genet Los Angeles CA 90095 USA

We studied the role of polypyrimidine tract binding protein in repressing splicing of the c-src neuronspecific N1 exon. Immunodepletion/add-back experiments demonstrate that PTB is essential for splicing repression in HeLa extract. When splicing is repressed, PTB cross-links to intronic CUCUCU elements flanking the N1 exon. Mutation of the downstream CLI elements causes dissociation of PTB from the intact upstream CU elements and allows splicing. Thus, PTB molecules bound to multiple elements cooperate to repress splicing. Interestingly, in neuronal WERI-1 cell extract where N1 is spliced, PTB also binds to the upstream CU elements but is dissociated in the presence of ATP. We conclude that splicing repression by PTB is modulated in different cells by a combination of cooperative binding and ATP-dependent dissociation.

关键词：腺苷三磷酸/代谢腺苷三磷酸/药理学结合部位细胞提取物外显子基因 src/遗传学 HeLa细胞内含子突变神经元/细胞学神经元/代谢器官特异性多聚嘧啶区结合蛋白质蛋白质结合/药物作用蛋白质结合/辐射效应 RNA前体/遗传学 RNA前体/代谢 RNA剪接/遗传学 RNA 信使/遗传学 RNA 信使/代谢 RNA结合蛋白质类/免疫学 RNA结合蛋白质类/代谢调控序列核酸/遗传学核糖核蛋白 U2小核/代谢核糖核蛋白类/免疫学核糖核蛋白类/代谢剪接体/代谢肿瘤细胞培养的紫外线人类

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c-src activates the DNA binding and transcriptional activity of Stat3 molecules: serine 727 is not required for transcriptional activation under certain circumstances

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 1999年第2期266卷 481-487页

作者： Schaefer, LK Wang, SG Schaefer, TS Univ Texas MD Anderson Canc Ctr Dept Neurosurg Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Dept Mol Genet Houston TX 77030 USA

Stat3 proteins are constitutively activated in cells transformed by v-src and the proteins have been shown to interact directly. Subsequent studies have shown that Stat3 is required for cellular transformation of MH fibroblasts by v-src, suggesting a potential role for Stat3 in aberrant cell growth. Stat3 is phosphorylated on a single tyrosine (tyrosine 705) which is required for effective dimer formation, An additional phosphorylation event (serine 727) is believed to be required for full transcriptional activity of Stat1 and Stat3 molecules. Here we report that c-src activates the DNA binding activity of Stat3 alpha, Stat3 beta, and three Stat3 mutants, one in which serine 727 was replaced by alanine (Stat3 alpha S727A) and C-terminal truncated molecules Delta 48 and Delta 55. Consistent with this finding is a general increase in the tyrosine 705-phosphorylated Stat3 in cells cotransfected with c-src. Furthermore, transcription from an alpha-2 macroglobulin reporter gene is activated by Stat3 alpha S727A to the same magnitude as compared to Stat3 alpha and Stat3 beta in the presence of c-src. These results suggest that serine 727, contained in a consensus MAP kinase recognition site and shown to be the only serine in Stat3 phosphorylated in epidermal growth factor (EGF) treated cells, is not necessary for transcriptional activity comparable to wild-type Stat3 alpha or Stat3 beta when activated by c-src in COS-7 cells. (C) 1999 Academic Press.

关键词：氨基酸序列 COS细胞 DNA结合蛋白质类/遗传学表皮生长因子/药理学基因报告基因 jun/遗传学基因 src/遗传学分子序列数据突变磷酰化 STAT3转录因子序列缺失反式激活因子类/遗传学转录遗传转染动物

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A role for the Hsp40 Ydj1 in repression of basal steroid receptor activity in yeast

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MOLECULAR AND CELLULAR BIOLOGY 2000年第9期20卷 3027-3036页

作者： Johnson, JL Craig, EA Univ Wisconsin Dept Biomol Chem Madison WI 53706 USA

In addition to its roles in translocation of preproteins across membranes, Ydj1 facilitates the maturation of Hsp90 substrates, including mammalian steroid receptors, which activate transcription in yeast in a hormone-dependent manner. To better understand Ydj1's function, we have constructed and analyzed an array of Ydj1 mutants in vivo. Both the glucocorticoid receptor and the estrogen receptor exhibited elevated activity in the absence of hormone in all ydj1 mutant strains, indicating a strict requirement for Ydj1 activity in hormonal control, Glucocorticoid receptor containing a mutation in the carboxy-terminal transcriptional activation domain, AF-2, retained elevated basal activity, while mutation of the amino-terminal transactivation domain, AF-1, eliminated the elevated basal activity observed in ydj1 mutant strains. This result indicates that the source of activity is AF-1, which is normally repressed by the carboxy-terminal hormone binding domain in the absence of hormone. Chimeric proteins containing the hormone binding domain of the estrogen or glucocorticoid receptor fused to heterologous activation and DNA binding domains also exhibited elevated activity in the absence of hormone. Thus, Ydj1 mutants appear to increase basal receptor activity by altering the ability of the hormone binding domain of the receptor to repress nearby activation domains. We propose that Ydj1 functions to present steroid receptors to the Hsp90 pathway for folding and hormonal control. In the presence of Ydj1 mutants that fail to bind substrate efficiently, some receptor escapes the Hsp90 pathway, resulting in constitutive activity.

关键词：电泳聚丙烯酰氨凝胶基因文库基因报告基因 src/遗传学 HSP40热休克蛋白质类 HSP70热休克蛋白质类/化学 HSP70热休克蛋白质类/遗传学 HSP70热休克蛋白质类/生理学 HSP90热休克蛋白质类/代谢热休克蛋白质类免疫印迹法诱变表型质粒蛋白质结构三级受体雌激素/代谢受体糖皮质激素/代谢受体类固醇/代谢重组融合蛋白质类/代谢酿酒酵母菌/代谢酿酒酵母蛋白质类温度双杂交系统技术 β半乳糖苷酶类/代谢

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Phylogenetic utility of the tyrosine kinase gene X-src for assessing relationships among representative cichlid fishes

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MOLECULAR PHYLOGENETICS AND EVOLUTION 2000年第1期14卷 51-74页

作者： Sides, J Lydeard, C Univ Alabama Dept Biol Sci Tuscaloosa AL 35487 USA

The nuclear gene X-src is a member of the tyrosine-kinase class of proto-oncogenes whose normal product is localized within the cytoplasm of the cell. The X-src gene has been used in only a few phylogenetic studies, each focusing on systematics of killifishes (Cyprinodontiformes), The present study is an attempt to examine the phylogenetic utility of X-src for uncovering relationships of representative cichlid fishes, especially the cichlids of Middle America, The family Cichlidae is a species-rich group of tropical freshwater fish made up of more than 1000 species which show a Gondwanan pattern of distribution. Cichlid fish have been the focus of numerous studies ranging from behavioral to biogeographical to systematic in nature, Particular emphasis has focused on the cichlids of the African Great Lakes and the explosive adaptive radiation of this group. However, Neotropical cichlids have received considerably less attention than their African counterparts. Our findings regarding the utility of X-src concur with those of previous phylogenetic analyses showing the exons of X-src to be highly conserved and useful mostly for revealing deep relationships among taxa. Like previous X-src studies, we also found the intron sequences of the gene to be variable in length and difficult to align across distantly related taxa but they provided useful information for resolving relationships among more closely related taxa. The X-src phylogeny supports the monophyly of Neotropical cichlids and cichlasomines groups A( =heroines) + B (=cichlasomines), A highly resolved tree is obtained within the heroines but little support is evident for most nodes based on the low number of unambiguous substitutions. The X-src gene is likely to be quite useful for resolving deep phylogenetic relationships such as those among major groups of actinopterygian fishes. (C) 2000 Academic Press.

关键词：碱基序列密码子保守序列外显子基因 src/遗传学内含子分子序列数据金鲈类/分类金鲈类/遗传学种系发生蛋白酪氨酸激酶类/遗传学序列分析 DNA 序列同源性核酸动物

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Early induction of angiogenetic signals in gliomas of GFAP-v-src transgenic mice

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AMERICAN JOURNAL OF PATHOLOGY 1999年第2期154卷 581-590页

作者： Theurillat, JP Hainfellner, J Maddalena, A Weissenberger, J Aguzzi, A Univ Zurich Hosp Dept Pathol Inst Neuropathol CH-8091 Zurich Switzerland

Angiogenesis is a prerequisite for solid tumor growth. Glioblastoma multiforme, the most common malignant brain tumor, is characterized by extensive vascular proliferation. We previously showed that transgenic mice expressing a GFAP-v-src fusion gene in astrocytes develop low-grade astrocytomas that progressively evolve into hypervascularized glioblastomas, Here, we examined whether tumor progression triggers angiogenetic signals. We found abundant transcription of vascular endothelial growth factor (VEGF) in neoplastic astrocytes at surprisingly early stages of tumorigenesis, VEGF and v-src expression patterns were not identical, suggesting that VEGF activation was not only dependent on v-src. Late-stage gliomas showed perinecrotic VEGF up-regulation similarly to human glioblastoma, Expression patterns of the endothelial angiogenic receptors flt-1, flk-1, tie-1, and tie-2 were similar to those described in human gliomas, but flt-1 was expressed also in neoplastic astrocytes, suggesting an autocrine role in tumor growth. In. crossbreeding experiments, hemizygous ablation of the tumor suppressor genes Rb and p53 had no significant effect on the expression of VEGF, flt-1, flk-1, tie-1, and tie-2, Therefore, expression of angiogenic signals is an early event during progression of GFAP-v-src tumors and precedes hypervascularization. Given the close similarities in the progression pattern between GFAP-v-src and human gliomas, the present results suggest that these mice may provide a useful tool for antiangiogenic therapy research.

关键词：人工基因融合星形细胞/代谢星形细胞/病理学星形细胞瘤/遗传学星形细胞瘤/代谢星形细胞瘤/病理学脑肿瘤/遗传学脑肿瘤/代谢脑肿瘤/病理学繁殖内皮生长因子/遗传学内皮生长因子/代谢基因视网膜母细胞瘤/遗传学基因 p53/遗传学基因 src/遗传学神经胶质原纤维酸性蛋白质/遗传学淋巴因子/遗传学淋巴因子/代谢小鼠转基因新生血管化病理性/遗传学新生血管化病理性/代谢新生血管化病理性/病理学原癌基因蛋白质类/遗传学原癌基因蛋白质类/代谢 RNA 信使/生物合成受体蛋白质酪氨酸激酶类/遗传学受体蛋白质酪氨酸激酶类/代谢受体 TIE-1 受体 TIE-2 受体细胞表面/遗传学受体细胞表面/代谢受体生长因子/遗传学受体生长因子/代谢受体 TIE 受体血管内皮生长因子信号传导血管内皮生长因子A 血管内皮生长因子受体1 血管内皮生长因子类动物女(雌)性男(雄)性小鼠

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Tyrosine kinase inhibitor research presses on despite halted clinical trial

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JOURNAL OF THE NATIONAL CANCER INSTITUTE 2000年第12期92卷 967-969页

作者： Garber, K

Successful drugs make headlines, but the failures quietly disappear from view. One experimental drug highly touted at previous American Association for Cancer Research meetings, Sugen Inc.’s SU-101, was notably absent from this year’s poster sessions. But in hallways and hotel rooms, news of the drug’s fate quickly spread by word of mouth: the South San Francisco-based biotech company had terminated the phase III clinical trial. Another cancer drug had failed. The news was especially disturbing, since SU-101 was in the vanguard of a class of drugs known as tyrosine kinase inhibitors. These agents have captivated oncologists because they are precisely targeted at cancer abnormalities and should be relatively nontoxic. And drug companies have embraced them with unprecedented eagerness: at least 18 tyrosine kinase inhibitors are in the clinic and scores are in preclinical development. Because SU-101 was the closest to FDA approval, its demise sent a shudder through the vast community of researchers working on these drugs. But SU-101’s fate “isn’t a showstopper for the entire field,” stressed Paul Workman, Ph.D., director of the Cancer Research Campaign Centre for Cancer Therapeutics in Surrey, England. “It simply means that particular molecule wasn’t right.” SU-101 had obvious problems, related to its tendency to be metabolized (and inactivated) quickly in the body, that were reported 2 years ago. So the field is likely to continue its forward surge with other agents that could become a breakthrough drug. Enzymes and Oncogenes Whichever tyrosine kinase inhibitor first wins marketing approval, it will be the culmination of a story that began 25 years ago, when tyrosine kinases—enzymes that can also be oncogenic—were first implicated in human cancer. The first oncogene, src, produced a tyrosine kinase. Its 1975 discovery by Harold Varmus, M.D., and Michael Bishop, M.D., was an early triumph of gene-based cancer research. Knowing that the src gene of the Rous sarcoma viru

关键词：药物临床试用/药理学酶抑制剂/药理学基因 src/遗传学吲哚类/药理学血小板源性生长因子/药物作用血小板源性生长因子/代谢蛋白酪氨酸激酶类/拮抗剂和抑制剂吡咯类/药理学受体蛋白质酪氨酸激酶类/药物作用受体蛋白质酪氨酸激酶类/代谢受体表皮生长因子/药物作用受体表皮生长因子/代谢受体生长因子/药物作用受体生长因子/代谢受体血管内皮生长因子信号传导/药物作用人类

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Lack of activating c-src mutations at codon 531 in rectal cancer

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CANCER GENETICS AND CYTOGENETICS 2000年第1期121卷 94-95页

作者： Nilbert, M Fernebro, E Univ Lund Hosp Dept Oncol S-22185 Lund Sweden

Cellular src (c-src), which is the human homolog of the Rous sarcoma viral oncogene, v-src, is highly activated in colorectal cancer. Recently, a subset of colon cancers have shown a nonsense mutation at codon 531, which truncates c-src directly C-terminal to the c-src kinase regulatory domain. This specific mutation has been demonstrated to be activating, transforming and tumorigenic and to promote metastasis. We investigated 100 rectal cancers, half of which had tumor spread outside the rectum, for this mutation by using direct sequencing. None of these tumors displaced any genetic alteration at this locus, and we thus conclude that the codon 531 mutation is a mle cause of c-src activation in rectal cancer. (C) 2000 Elsevier Science Inc. All rights reserved.

关键词：腺癌/遗传学密码子/生理学基因表达调控酶学/遗传学基因表达调控肿瘤/遗传学基因 src/遗传学突变/遗传学直肠肿瘤/遗传学成年人老年人老年人 80以上女(雌)性人类男(雄)性中年人

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