Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.17 (MMP-3)
 3,419 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell surface death receptor-mediated neuronal apoptosis, which is a critical component of neurodegeneration, is modulated by matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). Doxorubicin (Dox) induces neuronal death by the activation of death receptor pathways. Recently, we demonstrated that Dox-induced neuronal apoptosis is regulated by the balance of MMP-3 and TIMP-3 in rat cortical cultures. Inbred mouse strains exhibit differential susceptibility to cell death stimuli in vivo. Prior to employing transgenic approaches to further investigate the roles of TIMP-3 and MMP-3 in neuronal death, we examined whether inbred mice display strain-dependent vulnerability to Dox. We induced neuronal apoptosis with Dox in primary neuronal cultures established from cerebral cortices of embryonic day 15 C57BL/10 or C57BL/6 mice. Using fluorescence activated cell sorting for neurons, we found that C57BL/6 cortical cultures exhibit a 28% greater neuronal death following Dox treatment than C57BL/10. Real-time PCR of unstimulated cultures revealed that C57BL/10 cortical cultures have reduced basal mRNA levels encoding the pro-apoptotic proteins: Fas, FasL, and TIMP-3, but increased levels of the anti-apoptotic molecule MMP-3 as compared to C57BL/6. Furthermore, C57BL/10 cultures treated with Dox displayed an enhanced induction of mRNA transcripts that encode anti-apoptotic MMPs. These results show that C57BL/10 cortical cultures are more resistant to death receptor-mediated apoptotic cell death as compared to C57BL/6, and suggest that this difference is related to Fas, FasL, and MMP expression. Strain-dependent differences in response to apoptotic stimuli may be an important consideration for developing transgenic models of neurodegeneration.
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PMID:Vulnerability of mouse cortical neurons to doxorubicin-induced apoptosis is strain-dependent and is correlated with mRNAs encoding Fas, Fas-Ligand, and metalloproteinases. 1531 93

Malignant melanoma shows high levels of intrinsic drug resistance associated with a highly invasive phenotype. In this study, we investigated the role of the drug transporter P-glycoprotein (Pgp) in the invasion potential of drug-sensitive (M14 WT, Pgp-negative) and drug-resistant (M14 ADR, Pgp-positive) human melanoma cells. Coimmunoprecipitation experiments assessed the association of Pgp with the adhesion molecule CD44 in multidrug resistant (MDR) melanoma cells, compared with parental ones. In MDR cells, the two proteins colocalized in the plasma membrane as visualized by confocal microscopy and immunoelectron microscopy on ultrathin cryosections. MDR melanoma cells displayed a more invasive phenotype compared with parental cells, as demonstrated by quantitative transwell chamber invasion assay. This was accomplished by a different migration strategy adopted by resistant cells ("chain collective") previously described in tumor cells with high metastatic capacity. The Pgp molecule, after stimulation with specific antibodies, appeared to cooperate with CD44, through the activation of ERK1/2 and p38 mitogen-activated protein kinase (MAPK) proteins. This activation led to an increase of metalloproteinase (MMP-2, MMP-3, and MMP-9) mRNAs, and proteolytic activities, which are associated with an increased invasive behavior. RNA interference experiments further demonstrated Pgp involvement in migration and invasion of resistant melanoma cells. A link was identified between MDR transporter Pgp, and MAPK signaling and invasion.
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PMID:The multidrug transporter P-glycoprotein: a mediator of melanoma invasion? 1794 88