Data from Mouse Embryo Fibroblasts Lacking the Tumor Suppressor Menin Show Altered Expression of Extracellular Matrix Protein Genes

Abstract

<div>Abstract<p>Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant familial cancer syndrome characterized primarily by endocrine tumors of the parathyroids, anterior pituitary, and enteropancreatic endocrine tissues. Affected individuals carry a germ-line loss-of-function mutation of the <i>MEN1</i> gene, and tumors arise after loss of the second allele. Homozygous loss of <i>Men1</i> in the germ line of mice results in early embryonic lethality, with defective development of neural tube, heart, liver, and craniofacial structures. We generated immortalized wild-type (WT) and menin-null mouse embryo fibroblast (MEF) cell lines and evaluated their characteristics, including global expression patterns. The WT and menin-null cell lines were aneuploid, and the nulls did not display tumorigenic characteristics in soft agar assay. Expression arrays in menin-null MEFs revealed altered expression of several extracellular matrix proteins that are critical in organogenesis. Specifically, transcripts for fibulin 2 (<i>Fbln2</i>), periostin (<i>Postn</i>), and versican [chondroitin sulfate proteoglycan (<i>Cspg2</i>)], genes critical for the developing heart and known to be induced by transforming growth factor-β (TGF-β), were decreased in their expression in menin-null MEFs. <i>Fbln2</i> expression was the most affected, and the reduction in menin-null MEFs for <i>Fbln2, Postn</i>, and <i>Cspg2</i> was 16.18-, 5.37-, and 2.15-fold, respectively. Menin-null MEFs also showed poor response to TGF-β–induced Smad3-mediated transcription in a reporter assay, supporting a role for menin in this pathway. <i>Postn</i> and <i>Cspg2</i> expression in WT, unlike in null MEFs, increased on TGF-β treatment. The expression changes associated with the loss of the tumor suppressor menin provide insights into the defective organogenesis observed during early embryonic development in <i>Men1</i>-null mouse embryos. (Mol Cancer Res 2007;5(10):1041–51)</p></div>