Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuroblastoma (NBL) is the most common solid tumor in infants and accounts for 15% of all pediatric cancer deaths. Several risk factors predict NBL outcome: age at the time of diagnosis, stage, chromosome alterations and MYCN (V-Myc Avian Myelocytomatosis Viral Oncogene Neuroblastoma-Derived Homolog) amplification, which characterizes the subset of the most aggressive NBLs with an overall survival below 30%. MYCN-amplified tumors develop exceptional chemoresistance and metastatic capacity. These properties have been linked to defects in the apoptotic machinery, either by silencing components of the extrinsic apoptotic pathway (e.g. caspase-8) or by overexpression of antiapoptotic regulators (e.g. Bcl-2, Mcl-1 or FLIP). Very little is known on the implication of death receptors and their antagonists in NBL. In this work, the expression levels of several death receptor antagonists were analyzed in multiple human NBL data sets. We report that Lifeguard (LFG/FAIM2 (Fas apoptosis inhibitory molecule 2)/NMP35) is downregulated in the most aggressive and undifferentiated tumors. Intringuingly, although LFG has been initially characterized as an antiapoptotic protein, we have found a new association with NBL differentiation. Moreover, LFG repression resulted in reduced cell adhesion, increased sphere growth and enhanced migration, thus conferring a higher metastatic capacity to NBL cells. Furthermore, LFG expression was found to be directly repressed by MYCN at the transcriptional level. Our data, which support a new functional role for a hitherto undiscovered MYCN target, provide a new link between MYCN overexpression and increased NBL metastatic properties.
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PMID:MYCN repression of Lifeguard/FAIM2 enhances neuroblastoma aggressiveness. 2518 11

Lifeguard is an integral transmembrane protein that modulates FasL-mediated apoptosis by interfering with the activation of caspase 8. It is evolutionarily conserved, with homologues present in plants, nematodes, zebra fish, frog, chicken, mouse, monkey, and human. The Lifeguard homologue in Drosophila, CG3814, contains the Bax inhibitor-1 family motif of unknown function. Downregulation of Lifeguard disrupts cellular homeostasis and disease by sensitizing neurons to FasL-mediated apoptosis. We used bioinformatic analyses to identify CG3814, a putative homologue of Lifeguard, and knocked down CG3814/LFG expression under the control of the Dopa decarboxylase (Ddc-Gal4) transgene in Drosophila melanogaster neurons to investigate whether it possesses neuroprotective activity. Knockdown of CG3814/LFG in Ddc-Gal4-expressing neurons resulted in a shortened lifespan and impaired locomotor ability, phenotypes that are strongly associated with the degeneration and loss of dopaminergic neurons. Lifeguard interacts with anti-apoptotic Bcl-2 proteins and possibly pro-apoptotic proteins to exert its neuroprotective function. The co-expression of Buffy, the sole anti-apoptotic Bcl-2 gene family member in Drosophila, and CG3814/LFG by stable inducible RNA interference, suppresses the shortened lifespan and the premature age-dependent loss in climbing ability. Suppression of CG3814/LFG in the Drosophila eye reduces the number of ommatidia and increases disruption of the ommatidial array. Overexpression of Buffy, along with the knockdown of CG3814/LFG, counteracts the eye phenotypes. Knockdown of CG3814/LFG in Ddc-Gal4-expressing neurons in Drosophila diminishes its neuroprotective ability and results in a shortened lifespan and loss of climbing ability, phenotypes that are improved upon overexpression of the pro-survival Buffy.
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PMID:Knockdown of the putative Lifeguard homologue CG3814 in neurons of Drosophila melanogaster. 2800 5

Ovarian cancer is the main cause of gynecologic malignancy-related mortality in women. Therefore, the disease requires improvements in treatment options and in the potency of chemotherapeutic drugs. The study of apoptosis in tumor cells is an important field for cancer therapy and cancer molecular biology. It has recently been established that LFG-500, a new synthesized flavonoid with a piperazine and benzyl group substitution, has strong anticancer activity. However, its exact molecular mechanism is not fully understood. The present study aimed to examine the effects of LFG-500 on human ovarian cancer SKOV3 cells, as well as to identify its underlying mechanisms. The data showed that LFG-500 inhibited the growth of SKOV3 cells in a concentration-dependent manner. It was found that LFG-500 induced apoptosis in SKOV3 cells, detected by DAPI staining and an Annexin V/PI double-staining assay. Moreover, LFG-500 reduced caspase-3 protein expression and increased the Bcl-2-associated X protein/B-cell lymphoma 2 protein ratio. Further findings revealed that LFG-500 treatment resulted in reactive oxygen species (ROS) accumulation and loss of mitochondrial transmembrane potential. Collectively, these results demonstrated that LFG-500 efficiently induced apoptosis in SKOV3 cells, an event possibly associated with the trigging of the mitochondrial apoptotic pathway through ROS accumulation. Therefore, LFG-500 shows potential as a potent anticancer agent for the treatment of ovarian cancer.
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PMID:LFG-500, a newly synthesized flavonoid, induces apoptosis in human ovarian carcinoma SKOV3 cells with involvement of the reactive oxygen species-mitochondria pathway. 2858 46