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Figure 9 | BMC Molecular Biology

Figure 9

From: Use of adenoviral E1A protein to analyze K18 promoter deregulation in colon carcinoma cells discloses a role for CtBP1 and BRCA1

Figure 9

A model for the putative mechanism responsible for the differential activity of the K18 promoter and for the effect of the different E1A mutants. The E1A full-length protein is represented at the top with emphasis on the two domains of interest: aa 12 to 25 and the PLDLS motif. The horizontal line represents the DNA and the initiation site is symbolized by an arrow, whose thickness is an indication of the activity of the promoter. (A) Functioning of the K18 promoter in T and NT cells. The F factor is an as yet unidentified protein which has a HAT/FAT activity and is supposedly more abundant or more active in T cells (bold) than in NT cells. F acetylates (Ac) the substrate protein S, a non-histone protein whose acetylation level controls the activity of the K18 promoter. The acetylation level of S is also under the control of HDAC proteins. The CtBP1 protein interacts with the PLDLS motif of the CtIP protein. CtBP1 associates with some HDAC proteins by a domain that is different from the one recognizing the PLDLS motif [4, 48]. The recruited HDAC proteins deacetylate the S substrate in NT cells where the acetylase activity is already weak and this down-regulates the promoter. CtIP is an interaction partner of BRCA1 which is represented here as part of the preinitiation complex (PIC). (B) Effects of C-terminal deletion mutants of E1A on the activity of the K18 promoter in T and NT cells. The binding of these mutants to the F factor through the 12–25 domain results in a low HAT/FAT activity, deacetylation of S and inhibition of the promoter in T cells. These mutants are expected to have little effect in NT cells since the level of acetylation of S is already low in these cells. (C) Effects of N-terminal deletion mutants of E1A on the activity of the K18 promoter. The C-terminal part of E1A contains the PLDLS motif which permits its interaction with CtBP1. The displacement of CtBP1 from CtIP prevents the recruitment of HDAC proteins to the preinitiation complex. This is of no consequence in T cells where the S protein is maintained in an hyperacetylated state by the high HAT/FAT activity. In contrast, in NT cells removal of HDAC proteins allows the weak HAT/FAT activity to acetylate S to a high level which results in a stimulation of the promoter.

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