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Teifeld, Robert M.
Transient superinducibility of cyp1a1 mrna and transcription, and the dna elements responsible for mediating this effect

Order No. 9227181

The polycyclic aromatic hydrocarbon (PAH)-inducible CYP1A subfamily of cytochromes P450 is involved in the oxidative metabolism of a wide variety of endogenous and exogenous compounds, including carcinogens and other environmental contaminants. The expression of one member of the subfamily, the CYP1A1 gene, has previously been shown to be under transcriptional control modulated both by PAH-type inducers and by other factors. CYP1A1 transcription can also be superinduced by simultaneous treatment of certain cells in culture with PAH inducers and inhibitors of protein synthesis. In the present study we demonstrated that some cell types that are highly superinducible can be rendered unresponsive to cycloheximide if its addition is delayed approximately 1.5 hours after the cells are exposed to polycyclic aromatic hydrocarbons (Teifeld et al., 1989). This phenomenon, termed transient superinducibility, demonstrates that there are two phases to the initial transcriptional response of the CYP1A1 gene to polycyclic aromatic compounds: an early phase, during which inhibition of protein synthesis can augment the effect of inducers, and a later phase, during which inhibition of protein synthesis does not further increase CYP1A1 gene transcription rate. In order to identify the DNA elements which mediate this phenomenon we used chloramphenicol acetyltransferase (CAT) expression vector analysis.

These studies revealed that the region between $-$1.2 and $- $0.9 kb was necessary to mediate transient superinducibility in the NRK cell line. Further experiments with synthesized CYP1A1 sequences showed that the same elements responsible for mediating the inducible expression of the CYP1A1 gene by xenobiotic treatment, the two xenobiotic response elements, XRE1 and XRE2, were sufficient to mediate both superinduction and transient superinducibility. Loss of responsiveness to cycloheximide was correlated with the disappearance of Ah receptor/XRE binding activity from nuclear extracts of induced cells. Source: DAI, 53, no. 06B, (1992): 2700

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