Gene expression of the lysophosphatidic acid receptor 1 is a target of transforming growth factor beta

J Wu, A Mukherjee, D A Lebman, X Fang
Oncogene 2013 June 27, 32 (26): 3198-206
The lysophosphatidic acid (LPA) receptor LPA1/Edg2 is the first identified LPA receptor. Although its wide tissue distribution and biological functions have been well studied, little is known about how LPA1 is transcriptionally regulated. In the current study, we showed that LPA1 is a physiological target of transforming growth factor beta (TGFβ)-mediated repression. In both normal and neoplastic cells, TGFβ inhibits LPA1 promoter activity, LPA1 mRNA expression and LPA1-dependent chemotaxis and tumor cell invasion. Knockdown of the TGFβ intracellular effector Smad3 or Smad4 with lentivirally transduced short hairpin RNA relieved these inhibitory effects of TGFβ. Interestingly, the LPA1 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 LPA1 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 LPA1 gene promoter was further verified by chromatin immunoprecipitation assays. We therefore identified a novel role of TGFβ in the control of LPA1 expression and LPA1-coupled biological functions, adding LPA1 to the list of TGFβ-repressed target genes.

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