Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interactions between the protein kinase C and Chk1 inhibitor UCN-01 and rapamycin in human leukemia cells have been investigated in relation to apoptosis induction. Treatment of U937 monocytic leukemia cells with rapamycin (10 nmol/L) in conjunction with a minimally toxic concentration of UCN-01 (100 nmol/L) for 36 hours resulted in marked potentiation of mitochondrial injury (i.e., loss of mitochondrial membrane potential and cytosolic release of cytochrome c, AIF, and Smac/DIABLO), caspase activation, and apoptosis. The release of cytochrome c, AIF, and Smac/DIABLO were inhibited by BOC-D-fmk, indicating that their release was caspase dependent. These events were associated with marked down-regulation of Raf-1, MEK, and ERK phosphorylation, diminished Akt activation, and enhanced phosphorylation of c-Jun NH2-terminal kinase (JNK). Coadministration of UCN-01 and rapamycin reduced the expression levels of the antiapoptotic members of the Bcl-2 family Mcl-1 and Bcl-xL and diminished the expression of cyclin D1 and p34(cdc2). Furthermore, enforced expression of a constitutively active MEK1 or, to a lesser extent, myristoylated Akt construct partially but significantly attenuated UCN-01/rapamycin-mediated lethality in both U937 and Jurkat cell systems. Finally, inhibition of the stress-related JNK by SP600125 or by the expression of a dominant-negative mutant of c-Jun significantly attenuated apoptosis induced by rapamycin/UCN-01. Together, these findings indicate that the mammalian target of rapamycin inhibitor potentiates UCN-01 cytotoxicity in a variety of human leukemia cell types and suggest that inhibition of both Raf-1/MEK/ERK and Akt cytoprotective signaling pathways as well as JNK activation contribute to this phenomenon.
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PMID:Rapamycin and UCN-01 synergistically induce apoptosis in human leukemia cells through a process that is regulated by the Raf-1/MEK/ERK, Akt, and JNK signal transduction pathways. 1576 55

Peptidoglycan (PG) is detected in a high proportion in inflammatory cell-rich regions of human atheromatous plaques. In the present study, we determined the cellular factors involved in PG-mediated chemokine expression in mononuclear cells in order to understand the molecular mechanisms of inflammatory responses to bacterial pathogen-associated molecular patterns in the diseased artery. Exposure of human monocytic leukemia THP-1 cells to PG resulted in not only enhanced secretion of CCL2 and CCL4 but also profound induction of their gene transcripts, which were abrogated by oxidized 1-palmitoyl-2-arachidonosyl-sn-phosphatidylcholine, an inhibitor of Toll-like receptors (TLRs)-2/4, but not by polymyxin B. PG enhanced phosphorylation of Akt and mitogen-activated protein kinases and activated protein kinase C. Pharmacological inhibitors such as SB202190, SP6001250, U0126, Akt inhibitor IV, rapamycin, and RO318220 significantly attenuated PG-mediated up-regulation of CCL2 and CCL4. We propose that PG contributes to vascular inflammation in atherosclerotic plaques by upregulating expression of mononuclear cell chemoattractants via TLR-2, protein kinase C, Akt, mTOR, and mitogen-activated protein kinases.
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PMID:Peptidoglycan enhances secretion of monocyte chemoattractants via multiple signaling pathways. 2146 2