Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HIV protease inhibitor (PI)-associated cardiovascular risk, especially atherosclerosis, has become a major concern in the clinic. Macrophages are key players in the inflammatory response and atherosclerosis formation. We have previously shown that HIV PIs induce endoplasmic reticulum (ER) stress, activate the unfolded protein response (UPR), and increase the synthesis of the inflammatory cytokines, TNF-alpha and IL-6, by regulating the intracellular translocation of RNA binding protein HuR in macrophages. However, the underlying signaling mechanisms remain unclear. We show here that the HIV PI lopinavir significantly activated the extracellular-signal regulated protein kinase (ERK), but not c-Jun N-terminal kinase (JNK) and p38 MAPK. Lopinavir-induced cytosolic translocation of HuR and TNF-alpha and IL-6 synthesis was attenuated by specific chemical inhibitor of MEK (PD98058) or over-expression of dominant negative mutant of MEK1. In addition, we demonstrated that lopinavir-induced ERK activation and TNF-alpha and IL-6 expression were completely inhibited in macrophages from CHOP null mice. Taken together, these results indicate activation of the UPR plays an essential role in HIV PI-induced inflammatory cytokine synthesis and release by activating ERK, which increases the cytosolic translocation of HuR and subsequent binding to the 3'UTR of TNF-alpha and IL-6 mRNAs in macrophages.
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PMID:HIV protease inhibitor lopinavir-induced TNF-alpha and IL-6 expression is coupled to the unfolded protein response and ERK signaling pathways in macrophages. 1944 25

Recent studies suggest that HIV-1 protease inhibitors may have anti-neoplastic effects on some malignancies. The anti-neoplastic effects of lopinavir have not been established or studied in brain tumors. Primary cultures of three fetal leptomeninges and 18 meningiomas were treated with lopinavir alone or with PDGF-BB. DNA synthesis was assessed by CyQUANT. Lopinavir effects on basal and PDGF-stimulated phosphorylation of the Akt-mTOR, MEK1/2-MAPK and STAT3 pathways, phosphorylation of Rb, Caspase 3 activation and reductions in survivin were assessed by Western blots. Lopinavir produced a significant reduction in PDGF-BB stimulation of DNA synthesis in a leptomeningeal culture (P = 0.0013) and 1 of 6 WHO grade I and 1 of 4 grade II meningiomas at 24 h and in 3 of 6 WHO grade I, 4 of 4 grade II and 1 of 1 grade III cell cultures (P = 0.0001) at 72 h. Lopinavir reduced PDGF-BB stimulation of phosphorylation/activation of MAPK in the 22 week fetal leptomeningeal cell cultures and in cells from 1 grade I meningioma at 24 h, but in none of 4 grade I and 5 grade II meningiomas at 6 h. Lopinavir had no notable effect on basal or PDGF-stimulated p-mTOR, p-MEK1/2, or p-STAT3, activation of Caspase 3 or survivin levels. Lopinavir treatment for 24 h had no effect on basal Rb phosphorylation but reduced Rb phosphorylation in all four meningioma cultures. These studies suggest that lopinavir may inhibit meningioma growth, and does so in part by cell cycle arrest. Additional evaluation of lopinavir as a potential adjunct chemotherapy is warranted.
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PMID:Lopinavir inhibits meningioma cell proliferation by Akt independent mechanism. 2059 51