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Robertson, Richard William
Functional role of diverse sequence xenobiotic response elements (dxes) in regulation of cytochrome P-4501a1 (CYP1A1) gene transcription

Order No. 9636934

This dissertation presents evidence that activation of CYP1A1 gene transcription by aryl hydrocarbons is a multicomponent process involving interactions of the AH receptor complex (AHRC) with xenobiotic response elements (XREs) and interactions of secondary transcription factors with diverse sequence xenobiotic response elements (DXEs) and that interactions at DXEs are functionally important and are dependent on interactions of functional AHRC with XREs. Interactions at DXEs appear to be important due to the fact that DXEs can cooperate with XREs to confer on a reporter gene responsiveness to aryl hydrocarbons and the fact that the appearance of in vivo interactions at DXEs during activation parallels those at XREs as well as the fact that the kinetics of appearance of these interactions correlate with the levels of expression of P4501A1 mRNA in different cell lines. Dependence of interactions at DXEs on the interactions of functional AHRC with XREs is supported by the following findings: (1) Interactions at XREs and DXEs appear in parallel. (2) Down-regulation of the AH receptor leads to disappearance of footprints at XREs and DXEs. (3) Inhibition of protein synthesis which is known to prevent down-regulation of the AH receptor, preserves footprints at DXEs and XREs. (4) Cell line- specific differences in the kinetics of in vivo interactions at XREs are parallel at DXEs. (5) AHs fail to induce in vivo footprints at both XREs and DXEs in Hepa 1 mutant cells lacking functional nuclear AH receptor complex. (6) The appearance and disappearance of in vivo footprints at DXEs could not be correlated with changes in constitutive DXE-specific DNA- binding activities and instead correlated with changes in the DNA-binding activity of the AH receptor. The in vivo and in vitro findings reported here regarding the relationship between the interactions at XREs and DXEs are consistent with a chromatin remodelling mechanism during activation of CYP1A1 transcription which is induced by the activated AH receptor exposing previously inaccessible DXEs for interactions with constitutively present nuclear factors. Finally, a link is made between CYP1A1 gene regulation, the unified field described by physics and Maharishi's Vedic Science. Source: DAI, 57, no. 07B, (1996): 4210

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