Alternative promoter usage of the Fos-responsive gene Fit-1 generates mRNA isoforms coding for either secreted or membrane-bound proteins related to the IL-1 receptor

Abstract

Fit-1 has been identified previously as a Fos-responsive gene of rat fibroblasts. Here we show that Fit-1 is directly regulated by the estrogen-inducible transcription factor Fos-ER and that it belongs to the family of delayed early genes. Two different mRNA isoforms are expressed from the Fit-1 gene. The Fit-1M mRNA isolated from spleen codes for a membrane-bound protein which is most closely related in its extracellular, transmembrane and intracellular domains to the type I interleukin-1 (IL-1) receptor. The Fit-1S mRNA of fibroblasts directs, instead, the synthesis of a secreted protein consisting of only the extracellular domain. Analysis of the exon-intron structure of the Fit-1 gene indicated that the Fit-1S and Fit-1M mRNAs are transcribed from two different promoters and that the sequence differences at their 3' ends result from alternative 3' processing. Northern blot analysis with specific 5' and 3' probes directly demonstrated tight coupling between alternative promoter usage and 3' processing of the Fit-1 transcripts. The orthologous gene of the mouse (known as T1 or ST2) is expressed during ontogeny first in the fetal liver of the embryo and then in lung and hematopoietic tissues of the adult. The mRNA coding for the membrane-bound protein is more abundantly expressed in all of these tissues, while the transcript for the secreted form predominates in fibroblasts and mammary epithelial cells. Differential regulation of two distinct promoters is thus used to determine the ratio between secreted and membrane-bound forms of Fit-1 (T1/ST2) which may modulate signaling in response to IL-1.