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Reactivation of mutant p53 through interaction of a C-terminal peptide with the core domain 下载免费PDF全文
Selivanova G Ryabchenko L Jansson E Iotsova V Wiman KG 《Molecular and cellular biology》1999,19(5):3395-3402
A synthetic 22-mer peptide (peptide 46) derived from the p53 C-terminal domain can restore the growth suppressor function of mutant p53 proteins in human tumor cells (G. Selivanova et al., Nat. Med. 3:632-638, 1997). Here we demonstrate that peptide 46 binds mutant p53. Peptide 46 binding sites were found within both the core and C-terminal domains of p53. Lys residues within the peptide were critical for both p53 activation and core domain binding. The sequence-specific DNA binding of isolated tumor-derived mutant p53 core domains was restored by a C-terminal polypeptide. Our results indicate that C-terminal peptide binding to the core domain activates p53 through displacement of the negative regulatory C-terminal domain. Furthermore, stabilization of the core domain structure and/or establishment of novel DNA contacts may contribute to the reactivation of mutant p53. These findings should facilitate the design of p53-reactivating drugs for cancer therapy. 相似文献
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Large-scale bioethanol production from lignocellulosic biomass will require high solids loading in the enzymatic hydrolysis step. However, slurries of pretreated lignocelluloses are complex fluids due to the fibrous nature, especially at high concentrations of water insoluble solids (WIS). A prerequisite for dealing with transport issues and for developing efficient full-scale processes is a fundamental understanding of the flow properties of pretreated lignocellulose. A comprehensive rheological characterization of dilute acid pretreated spruce has been carried out in this study, accounting for the effects of WIS concentration, particle size distribution (PSD), and the degree of enzymatic hydrolysis. The rheology of pretreated spruce slurries was found to be strongly dependent on the WIS concentration. The storage modulus (G'(LVR)) and yield stress showed typical power-law dependencies on volume fraction and WIS content. Milling of the pretreated material resulted in significantly higher yield stress and viscosity, likely due to narrower PSD, which suggests that the strength of the network of the coarsest fibers determines the rheology of these materials to a large extent. During enzymatic hydrolysis, yield stress and viscosity decreased dramatically, partly due to decreasing WIS content, but possibly also due to changes in fiber properties such as the chemical composition. 相似文献
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The TP53 tumor suppressor gene is mutated in many human tumors, including common types of cancer such as colon and ovarian cancer. This illustrates the key role of p53 as trigger of cell cycle arrest or cell death upon oncogenic stress. Most TP53 mutations are missense mutations that result in single amino acid substitutions in p53 and expression of high levels of dysfunctional p53 protein. Restoration of wild type p53 function in such tumor cells will induce robust cell death and allow efficient eradication of the tumor. Therapeutic targeting of mutant p53 in tumors is a rapidly developing field at the forefront of translational cancer research. Various approaches have led to the identification of small molecules that can rescue mutant p53. These include compounds that target specific p53 mutations, including PK083 and PK5174 (Y220C mutant p53) and NSC319726 (R175H mutant p53), as well as PRIMA-1 and its analog APR-246 that affect a wider range of mutant p53 proteins. APR-246 has been tested in a Phase I/II clinical trial with promising results. 相似文献
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Ligand-dependent regulation of intracellular protein transport: effect of vitamin a on the secretion of the retinol-binding protein 总被引:10,自引:4,他引:6 下载免费PDF全文
H Ronne C Ocklind K Wiman L Rask B Obrink P A Peterson 《The Journal of cell biology》1983,96(3):907-910
As a model of ligand-dependent protein secretion the biosynthesis, intracellular transport, and release of the retinol-binding protein (RBP) were studied in primary cultures of rat hepatocytes pulse-labeled with [35S]methionine. After various periods of chase RBP was isolated by immunoprecipitation and identified by SDS PAGE. Both normal and vitamin A-deficient hepatocytes synthesized RBP. The normal cells secreted the pulse-labeled RBP within 2 h. RBP synthesized by deficient cells was not secreted, and intracellular degradation of the protein appeared to be slow. Deficient cells could be induced to secrete RBP on the addition of retinol to the culture medium. This occurred also after protein synthesis had been blocked by cycloheximide. Since retinol induces the secretion of RBP, accumulated in the endoplasmic reticulum (ER), it seems reasonable to conclude that the transport of RBP from the ER to the Golgi complex is regulated by retinol. 相似文献