Gene Expression of the Lysophosphatidic Acid Receptor 1 Is a Target of Transforming Growth Factor Beta

The lysophosphatidic acid (LPA) receptor LPA(1)/Edg2 is the first identified LPA receptor. Although its wide tissue distribution and biological functions have been well studied, little is known about how LPA(1) is transcriptionally regulated. In the current study, we showed that LPA(1) is a physiological target of transforming growth factor beta (TGFβ)-mediated repression. In both normal and neoplastic cells, TGFβ inhibits LPA(1) promoter activity, LPA(1) mRNA expression, and LPA(1)-dependent chemotaxis and tumor cell invasion. Knockdown of the TGFβ intracellular effector Smad3 or Smad4 with lentivirally transduced shRNA relieved these inhibitory effects of TGFβ. Interestingly, the LPA(1) promoter contains two potential TGFβ inhibitory elements (TIEs), each consisting of a Smad binding site and an adjacent E2F4/5 element, structurally similar to the TIE found on the promoter of the well-defined TGFβ target gene c-myc. Deletion and point mutation analyses indicate that the distal TIE located at 401 bp from the transcription initiation site, is required for TGFβ repression of the LPA(1) promoter. A DNA pull-down assay showed that the -401 TIE was capable of binding Samd3 and E2F4 in TGFβ-treated cells. TGFβ-induced binding of the Smad complex to the native -401 TIE sequence of the LPA(1) gene promoter was further verified by chromatin immunoprecipitation assays. We therefore identified a novel role of TGFβ in the control of LPA(1) expression and LPA(1)-coupled biological functions, adding LPA(1) to the list of TGFβ-repressed target genes.