ABSTRACT
The expression of ßIII-tubulin (TUBB3) is generally restricted to neurons, but its mRNA is often expressed at low levels in non-neuronal cells. Interestingly, however, a number of non-neural tumors occasionally express high levels of TUBB3 protein, leading to a significant resistance to taxane derivatives. However, the molecular mechanisms controlling TUBB3 expression and its turnover during normal cell growth are largely unknown. Here, we present evidence that TUBB3 expression occurs in a cell cycle-dependent manner, and that its protein levels are controlled by the ubiquitin-proteasome system. Both mRNA and protein of TUBB3 accumulated around the G2/M stage of the cell cycle, and reduction of TUBB3 expression by siRNA resulted in partial inhibition of cell growth. Furthermore, the cell cycle-dependent expression of TUBB3 was mediated by the RE-1-silencing transcription factor REST through its binding to the RE-1 element that is present in the first intron of the TUBB3 gene. These results demonstrate a novel role of TUBB3 in cell cycle progression in non-neuronal cells, and further suggest that dysregulation of the REST-TUBB3 system could be a primary cause of the TUBB3 overexpression.
Subject(s)
Cell Division/genetics , G2 Phase/genetics , Gene Expression Regulation, Neoplastic , Tubulin/biosynthesis , Tubulin/genetics , Cell Line, Transformed , Cell Line, Tumor , Cell Proliferation , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Epigenomics/methods , HEK293 Cells , HeLa Cells , Humans , Introns/genetics , Proteasome Endopeptidase Complex/metabolism , RNA, Messenger/genetics , RNA, Small Interfering/genetics , Repressor Proteins/metabolism , Tubulin/metabolism , Ubiquitin/metabolismABSTRACT
UNLABELLED: It is important to take into consideration the duration for which the plasma concentration of the drug is higher than the Minimal Inhibitory Concentration during treatment with carbapenem antibiotics, because the antibiotics are time-dependent drugs. A preliminary study of the administration of carbapenem antibiotics on the basis of the pharmacokinetics/pharmacodynamics (PK/PD) was conducted. SUBJECTS: Ten patients with intraabdominal infection. METHODS: The patients were divided into two groups: the first group was assigned to administration of a carbapenem antibiotic (meropenem) at a daily dose of 0.5 g in 3 divided doses, each dose by intravenous infusion over 3 hours (Group 3 H), and the other group was assigned to administration of each dose over 30 minutes (Group 30 M). The body temperature (BT), white blood cell count (WBC), serum C-reactive protein (CRP) level, and the systemic inflammatory reactive syndrome (SIRS) score before and 96 hours after the drug administration were compared between Group 3 H and Group 30 M. RESULTS: There were 5 patients (mean age, 67.4+/-14.6 years) in Group 3H and 5 patients (mean age, 60.0+/-12.8 years) in Group 30 M. The evaluated parameters (BT, WBC, CRP, SIRS score) before the drug administration in Groups 3 H and 30M were not significant. Group 3 H showed significant decreases in the SIRS scores at 96 hours after the drug administration, however, there were no significant differences in the BT, WBC or CRP between the two groups. DISCUSSION: Group 3 H showed early improvement in the SIRS scores. Administration of carbapenem antibiotics based on the PK/PD is important, and requires further studies.
