Gene/Protein Disease Symptom Drug Enzyme Compound
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 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bcl-2 belongs to a family of apoptosis-regulatory proteins which incorporate into the outer mitochondrial as well as nuclear membranes. The mechanism by which the proto-oncogene product Bcl-2 inhibits apoptosis is thus far elusive. We and others have shown previously that the first biochemical alteration detectable in cells undergoing apoptosis, well before nuclear changes become manifest, is a collapse of the mitochondrial inner membrane potential (delta psi m), suggesting the involvement of mitochondrial products in the apoptotic cascade. Here we show that mitochondria contain a pre-formed approximately 50-kD protein which is released upon delta psi m disruption and which, in a cell-free in vitro system, causes isolated nuclei to undergo apoptotic changes such as chromatin condensation and internucleosomal DNA fragmentation. This apoptosis-inducing factor (AIF) is blocked by N-benzyloxycarbonyl-Val-Ala-Asp.fluoromethylketone (Z-VAD.fmk), an antagonist of interleukin-1 beta-converting enzyme (ICE)-like proteases that is also an efficient inhibitor of apoptosis in cells. We have tested the effect of Bcl-2 on the formation, release, and action of AIF. When preventing mitochondrial permeability transition (which accounts for the pre-apoptotic delta psi m disruption in cells), Bcl-2 hyperexpressed in the outer mitochondrial membrane also impedes the release of AIF from isolated mitochondria in vitro. In contrast, Bcl-2 does not affect the formation of AIF, which is contained in comparable quantities in control mitochondria and in mitochondria from Bcl-2-hyperexpressing cells. Furthermore, the presence of Bcl-2 in the nuclear membrane does not interfere with the action of AIF on the nucleus, nor does Bcl-2 hyperexpression protect cells against AIF. It thus appears that Bcl-2 prevents apoptosis by favoring the retention of an apoptogenic protease in mitochondria.
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PMID:Bcl-2 inhibits the mitochondrial release of an apoptogenic protease. 887 5

Astaxanthin (AST), a xanthophylls carotenoid, possesses significant anticancer effects. However, to date, the molecular mechanism of anticancer remains unclear. In the present research, we studied the anticancer mechanism of AST, including the changes in cell ultrastructure, such as the mitochondrion, rough endoplasmic reticulum (RER), Golgi complex, and cytoskeleton, the inhibition of Janus kinase 1(JAK1)/transduction and the activators of the transcription-3 (STAT3) signaling pathway using rat hepatocellular carcinoma CBRH-7919 cells. Cell apoptosis was evaluated and the expressions of JAK1, STAT3, non-metastasis23-1 (nm23-1), and apoptotic gene like B-cell lymphoma/leukemia-2 (bcl-2), B-cell lymphoma-extra large (bcl-xl), proto-oncogene proteins c myc (c-myc) and bcl-2- associated X (bax) were also examined. The results showed that AST could induce cancer cell apoptosis. Under transmission electron microscope, the ultrastructure of treated cells were not clearly distinguishable, the membranes of the mitochondrion, RER, Golgi complex were broken or loosened, and the endoplasmic reticulum (ER) was degranulated. Cytoskeleton depolymerization of the microtubule system led to the collapse of extended vimentin intermediate filament bundles into short agglomerations with disordered distributions. AST inhibited the expression of STAT3, its upstream activator JAK1, and the STAT3 target antiapoptotic genes bcl-2, bcl-xl, and c-myc. Conversely, AST enhanced the expressions of nm23-1 and bax. Overall, our findings demonstrate that AST could induce the apoptosis of CBRH-7919 cells, which are involved in cell ultrastructure and the JAK1/STAT3 signaling pathway.
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PMID:Changes in cell ultrastructure and inhibition of JAK1/STAT3 signaling pathway in CBRH-7919 cells with astaxanthin. 2288 54

The MYCN proto-oncogene is associated with poor outcome across a broad range of pediatric tumors. While amplification of MYCN drives subsets of high-risk neuroblastoma and medulloblastoma, dysregulation of MYCN in medulloblastoma (in the absence of amplification) also contributes to pathogenesis. Since PI3K stabilizes MYCN, we have used inhibitors of PI3K to drive degradation. In this study, we show PI3K inhibitors by themselves induce cell cycle arrest, with modest induction of apoptosis. In screening inhibitors of PI3K against MYCN, we identified PIK-75 and its derivative, PW-12, inhibitors of both PI3K and of protein kinases, to be highly effective in destabilizing MYCN. To determine the effects of PW-12 treatment in vivo, we analyzed a genetically engineered mouse model for MYCN-driven neuroblastoma and a model of MYCN-driven medulloblastoma. PW-12 showed significant activity in both models, inducing vascular collapse and regression of medulloblastoma with prominent apoptosis in both models. These results demonstrate that inhibitors of lipid and protein kinases can drive apoptosis in MYCN-driven cancers and support the importance of MYCN as a therapeutic target.
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PMID:Downregulation of MYCN through PI3K Inhibition in Mouse Models of Pediatric Neural Cancer. 2602 67

The production of high-affinity antibodies by B cells is essential for pathogen clearance. Antibody affinity for antigen is increased through the affinity maturation in germinal centers (GCs). This is an iterative process in which B cells cycle between proliferation coupled with the acquisition of mutations and antigen-based positive selection, resulting in retention of the highest-affinity B cell clones. The posttranscriptional regulator microRNA-155 (miR-155) is critical for efficient affinity maturation and the maintenance of the GCs; however, the cellular and molecular mechanism by which miR-155 regulates GC responses is not well understood. Here, we utilized a miR-155 reporter mouse strain and showed that miR-155 is coexpressed with the proto-oncogene encoding c-MYC in positively selected B cells. Functionally, miR-155 protected positively selected c-MYC+ B cells from apoptosis, allowing clonal expansion of this population, providing an explanation as to why Mir155 deletion impairs affinity maturation and promotes the premature collapse of GCs. We determined that miR-155 directly inhibits the Jumonji family member JARID2, which enhances B cell apoptosis when overexpressed, and thereby promotes GC B cell survival. Our findings also suggest that there is cooperation between c-MYC and miR-155 during the normal GC response, a cooperation that may explain how c-MYC and miR-155 can collaboratively function as oncogenes.
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PMID:MicroRNA-155 controls affinity-based selection by protecting c-MYC+ B cells from apoptosis. 2665 56