Cyclin-dependent kinase inhibitors are proteins with functions which appear to involve regulation of cell cycle traverse, and have been suggested to have a role in cell differentiation. However, there is as yet no rigorous proof that this is the case. We have addressed the participation of one of these inhibitors, p27Kip1 , in the induction of differentiation and the subsequent G1 block induced in HL60 cells by 1,25-dihydroxyvitamin D 3 (1,25D 3 ). First, it was noted that sublines of HL60 cells able to grow rapidly in the presence of 1,25D 3 have protein levels of p27Kip1 lower than the levels in cells subjected to 1,25D 3 -induced growth inhibition, but higher than in untreated parental cells. In contrast, there was no discernible relationship between the levels of p27Kip1 and the expression of differentiation markers. Further, HL60 cells treated with 1,25D 3 and an oligonucleotide antisense, but not mismatched, to p27 Kip1showed an almost complete elimination of the 1,25D 3 -induced G1 block, but no decrease in the expression of differentiation markers. Similar results were obtained following transient transfection with an expression vector bearing the entire p27Kip1 coding sequence in the anti-sense orientation. This is the first direct demonstration that p27Kip1 plays a role in the 1,25D 3 -induced G1 arrest, and that partial reduction in its levels has no effect on the induction of differentiation in HL60 cells.
ABSTRACT. Sevoflurane, the most widely used anesthetic in clinical practice, has been shown to induce apoptosis, inhibit neurogenesis, and cause learning and memory impairment in young mice. However, the underlying mechanism is still unknown. In this study, wild-type and the FAS-or FAS ligand (FASL)-knockout mice (age 7 days) were exposed to sevoflurane or pure oxygen. Western blotting was used to examine the expression of FAS protein.Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) and bromodeoxyuridine (BrdU) staining were employed to quantify the apoptotic cells and newborn cells in the hippocampus and Morris water maze (MWM) in order to evaluate learning and memory status. Sevoflurane significantly increased the expression of FAS protein in wild-type mice. Compared to FASand FASL-knockout mice treated with sevoflurane, sevoflurane-treated wildtype mice exhibited more TUNEL-positive hippocampal cells and less BrdU- (2015) positive hippocampal cells. The MWM showed that compared with FAS-and FASL-knockout mice treated with sevoflurane, sevoflurane treatment of wildtype mice significantly prolonged the escape latency and reduced platform crossing times. These data suggest that sevoflurane induces neurotoxicity in young mice through FAS-FASL signaling.
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