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Retinoic Acid Upregulates Cone Arrestin Expression in Retinoblastoma Cells through a Cis Element in the Distal Promoter Region

From The Mary D. Allen Laboratory for Vision Research, Doheny Eye Institute, and Department of Cell and Neurobiology, The Keck School of Medicine of the University of Southern California, Los Angeles, California.

PURPOSE. This study was initiated to investigate the molecular mechanisms of activation of expression of the human cone arrestin (hCAR) gene by retinoic acid (RA), in an in vitro model of retinoblastoma cells.

METHODS. Human retinoblastoma Weri-Rb-1 or Y79 cell lines were cultured in the absence or presence of RA analogues with transcription or translation inhibitors for various periods. The mRNAs encoding hCAR, retinoic acid receptor (RAR), and retinoid X receptor (RXR) subtypes were analyzed by Northern blot. Immunoblot analysis of hCAR protein was also performed. The hCAR promoter’s activity and its responsiveness to RA treatment was evaluated by transient transfection of the hCAR promotor-luciferase reporter constructs, followed by promoter deletion analysis to map the specific regions responsible for the RA response.

RESULTS. In our in vitro model, both all-trans RA and 9-cis RA induced hCAR mRNA in a time- and dose-dependent manner. RA’s effect was blocked by either RNA or protein synthesis inhibitors; however, hCAR mRNA’s stability was not affected by RA, as determined by RNA decay experiments. Although all RAR and RXR subtypes were detected, only RXR and RAR increased dramatically after treatment with RA. An RXR-specific agonist, but not an RAR-specific agonist, also increased hCAR mRNA and protein expression in both Weri-Rb-1 and Y79 cells. RA stimulated hCAR promoter-luciferase activity in transient transfection studies. Subsequently, a region between –852 and –702 of the hCAR promoter, with RA-responsive elements (RAREs), was discovered to be responsible for the RA response.

CONCLUSIONS. The hCAR gene is transcriptionally upregulated by RA acting through cis elements within –852 to –702 of the hCAR 5' flanking region. Based on the cumulative data, RXR is most likely the RA receptor subtype involved in hCAR regulation by RA.

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