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Activation of the Polycystic Kidney Disease‐1 (PKD1) Promoter by Retinoic Acid: Involvement of Sp1.

We found that all‐trans retinoic acid (AT‐RA), 9‐cis retinoic acid (9C‐RA) and their receptors (RAR or RXR) significantly induced transcriptional activity (up to >10 fold) from the 200 bp proximal PKD1 (Polycystic Kidney Disease 1) promoter in HEK293T, COS‐1, and HCT116 cells. This fragment lacks a canonical RAR/RXR motif but contains six GC box motifs. Analysis of the GC boxes revealed that a combination of three sites is involved in the activation by retinoids. Mithramycin A, which inhibits Sp1 binding, and Sp1siRNA completely blocked transcriptional up‐regulation by AT‐RA and RXR. Furthermore, in Drosophila SL2 cells lacking Sp1, the 200 bp proximal promoter could not be induced by AT‐RA, but could be strongly activated with exogenous Sp1. As determined by RT‐PCR, AT‐RA treatment of HEK293T cells (5 μM for 40 hrs) increased the levels of endogenous PKD1 mRNA 1.6 fold (p<0.05). Chromatin immunoprecipitation (ChIP)‐PCR assays using anti‐RXR antibody suggested that RXR is bound, directly or indirectly, to a sequence present within this fragment. Taken together, these data indicate that induction of the PKD1 promoter by RA is mediated through several GC boxes in the proximal promoter, possibly by Sp1, and suggest that retinoids and their nuclear receptors may play a role in PKD1 gene regulation. This is the first report of hormonal regulation of the PKD1 promoter.