共查询到20条相似文献,搜索用时 0 毫秒
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Hiroki Takahashi Monica C. Chen Hung Pham Yoichi Matsuo Hideyuki Ishiguro Howard A. Reber Hiromitsu Takeyama Oscar J. Hines Guido Eibl 《Biochimica et Biophysica Acta (BBA)/Molecular Cell Research》2013,1833(12):2980-2987
Anti-apoptotic Bcl-2 family proteins have been reported to play an important role in apoptotic cell death of human malignancies. The aim of this study was to delineate the mechanism of anti-apoptotic Bcl-2 family proteins in pancreatic cancer (PaCa) cell survival. We first analyzed the endogenous expression and subcellular localization of anti-apoptotic Bcl-2 family proteins in six PaCa cell lines by Western blot. To delineate the functional role of Bcl-2 family proteins, siRNA-mediated knock-down of protein expression was used. Apoptosis was measured by Cell Death ELISA and Hoechst 33258 staining. In the results, the expression of anti-apoptotic Bcl-2 family proteins varied between PaCa cell lines. Mcl-1 knock-down resulted in marked cleavage of PARP and induction of apoptosis. Down-regulation of Bcl-2 or Bcl-xL had a much weaker effect. Simultaneous knock-down of Bcl-xL and Mcl-1 strongly induced apoptosis, but simultaneous knock-down of Bcl-xL/Bcl-2 or Mcl-1/Bcl-2 had no additive effect. The apoptosis-inducing effect of simultaneous knock-down of Bcl-xL and Mcl-1 was associated with translocation of Bax from the cytosol to the mitochondrial membrane, cytochrome c release, and caspase activation. These results demonstrated that Bcl-xL and Mcl-1 play an important role in pancreatic cancer cell survival. Targeting both Bcl-xL and Mcl-1 may be an intriguing therapeutic strategy in PaCa. 相似文献
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DNA binding proteins recognize DNA specifically or non-specifically using direct and indirect readout mechanisms like sliding, hopping, and diffusion. However, a common difficulty in explicitly elucidating any particular mechanism of site-specific DNA-protein recognition is the lack of knowledge regarding target sequences and inadequate account of non-specific interactions, in general. Here, we decipher the structural basis of target search performed by the key regulator of expression of c-myc proto-oncogene, the human RBMS1 protein. In this study, we have shown the structural reorganization of this multi-domain protein required for recognizing the specific c-myc promoter sequence. The results suggest that a synergy between structural re-organization and thermodynamics is necessary for the recognition of target sequences. The study presents another perspective of looking at the DNA-protein interactions. 相似文献
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Identification of binding sites of EVI1 in mammalian cells 总被引:4,自引:0,他引:4
Yatsula B Lin S Read AJ Poholek A Yates K Yue D Hui P Perkins AS 《The Journal of biological chemistry》2005,280(35):30712-30722
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The RET proto-oncogene induces apoptosis: a novel mechanism for Hirschsprung disease 总被引:15,自引:0,他引:15 下载免费PDF全文
Bordeaux MC Forcet C Granger L Corset V Bidaud C Billaud M Bredesen DE Edery P Mehlen P 《The EMBO journal》2000,19(15):4056-4063
The RET (rearranged during transfection) proto-oncogene encodes a tyrosine kinase receptor involved in both multiple endocrine neoplasia type 2 (MEN 2), an inherited cancer syndrome, and Hirschsprung disease (HSCR), a developmental defect of enteric neurons. We report here that the expression of RET receptor induces apoptosis. This pro-apoptotic effect of RET is inhibited in the presence of its ligand glial cell line-derived neurotrophic factor (GDNF). Furthermore, we present evidence that RET induces apoptosis via its own cleavage by caspases, a phenomenon allowing the liberation/exposure of a pro-apoptotic domain of RET. In addition, we report that Hirschsprung-associated RET mutations impair GDNF control of RET pro-apoptotic activity. These results indicate that HSCR may result from apoptosis of RET-expressing enteric neuroblasts. 相似文献
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Newman DK Hoffman S Kotamraju S Zhao T Wakim B Kalyanaraman B Newman PJ 《Biochemical and biophysical research communications》2002,296(5):1171-1179
Platelet-endothelial cell adhesion molecule-1 (PECAM-1) is a cell adhesion molecule with a cytoplasmic immunoreceptor tyrosine-based inhibitory motif (ITIM) that, when phosphorylated, binds Src homology 2 domain-containing protein-tyrosine phosphatase (SHP-2). PECAM-1 is expressed at endothelial cell junctions where exposure to inflammatory intermediates may result in post-translational amino acid modifications that affect protein structure and function. Reactive nitrogen species (RNS), which are produced at sites of inflammation, nitrate tyrosine residues, and several proteins modified by tyrosine nitration have been found in diseased tissue. We show here that the RNS, peroxynitrite, induced nitration of both full-length cellular PECAM-1 and a purified recombinant PECAM-1 cytoplasmic domain. Mass spectrometric analysis of tryptic fragments revealed quantitative nitration of ITIM tyrosine 686. A synthetic peptide containing 3-nitrotyrosine at position 686 could not be phosphorylated nor bind SHP-2. These data suggest that ITIM tyrosine nitration may represent a mechanism for modulating phosphotyrosine-dependent signal transduction pathways. 相似文献
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T Kodama H Hikita T Kawaguchi M Shigekawa S Shimizu Y Hayashi W Li T Miyagi A Hosui T Tatsumi T Kanto N Hiramatsu K Kiyomizu S Tadokoro Y Tomiyama N Hayashi T Takehara 《Cell death and differentiation》2012,19(11):1856-1869
Anti-apoptotic Bcl-2 family proteins, which inhibit the mitochondrial pathway of apoptosis, are involved in the survival of various hematopoietic lineages and are often dysregulated in hematopoietic malignancies. However, their involvement in the megakaryocytic lineage is not well understood. In the present paper, we describe the crucial anti-apoptotic role of Mcl-1 and Bcl-xL in this lineage at multistages. The megakaryocytic lineage-specific deletion of both, in sharp contrast to only one of them, caused apoptotic loss of mature megakaryocytes in the fetal liver and systemic hemorrhage, leading to embryonic lethality. ABT-737, a Bcl-xL/Bcl-2/Bcl-w inhibitor, only caused thrombocytopenia in adult wild-type mice, but further induced massive mature megakaryocyte apoptosis in the Mcl-1 knockout mice, leading to severe hemorrhagic anemia. All these phenotypes were fully restored if Bak and Bax, downstream apoptosis executioners, were also deficient. In-vitro study revealed that the Jak pathway maintained Mcl-1 and Bcl-xL expression levels, preventing megakaryoblastic cell apoptosis. Similarly, both were involved in reticulated platelet survival, whereas platelet survival was dependent on Bcl-xL due to rapid proteasomal degradation of Mcl-1. In conclusion, Mcl-1 and Bcl-xL regulate the survival of the megakaryocytic lineage, which is critically important for preventing lethal or severe hemorrhage in both developing and adult mice. 相似文献
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WT1 modulates apoptosis by transcriptionally upregulating the bcl-2 proto-oncogene. 总被引:16,自引:0,他引:16 下载免费PDF全文
M W Mayo C Y Wang S S Drouin L V Madrid A F Marshall J C Reed B E Weissman A S Baldwin 《The EMBO journal》1999,18(14):3990-4003
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Yu-Sheng Chen Hong-Ru Li Ming Lin Gang Chen Bao-Song Xie Neng-Luan Xu Li-Fang Lin 《Molecular biology reports》2010,37(5):2241-2247
Livin, a novel member of inhibitors of apoptosis protein, is highly expressed in tumor tissues. It is a potential target in
tumor therapy. Silencing its gene expression has been found to promote tumor cell apoptosis or increase tumor sensitivity
to therapies. This paper studied the effect of livin anti-apoptotic activity and examined its molecular mechanisms. In the
study, higher levels of cell apoptosis were measured by FACS in the experiment group with livin expression silenced than that
in controls (P < 0.05). After livin gene expression was knocked down, cleaved caspase-3 protein was up-regulated but caspase-3 mRNA expression
was almost the same, the phosphorylated JNK1 protein was down-regulated but JNK1 mRNA and total JNK1 protein expression was
approximately the same too. The results suggest that livin may exert anti-apoptotic action on SPC-A1 by activating JNK1 signaling
pathway and inhibiting caspase-3 activation. 相似文献
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5-FU preferably induces apoptosis in BRAF V600E colorectal cancer cells via downregulation of Bcl-xL
Shi Tongfei Gao Mohan He Meihui Yue Fengli Zhao Yawei Sun Madi He Kan Chen Li 《Molecular and cellular biochemistry》2019,460(1-2):151-164
Molecular and Cellular Biochemistry - Diallyl trisulfide (DATS) is distinguished as the most potent polysulfide isolated from garlic. The aim of our study was to investigate effects of oral... 相似文献