Mouse embryo fibroblasts lacking the tumor suppressor menin show altered expression of extracellular matrix protein genes

Youngmi Ji, Nijaguna B. Prasad, Elizabeth A. Novotny, Sukhbir Kaur, Abdel Elkahloun, Yidong Chen, Rui Zhu Zhang, Mon Li Chu, Sunita K. Agarwal, Stephen J. Marx, Francis S. Collins, Settara C. Chandrasekharappa

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15 Scopus citations

Abstract

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 MEN1 gene, and tumors arise after loss of the second allele. Homozygous loss of Men1 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 (Fbln2), periostin (Postn), and versican [chondroitin sulfate proteoglycan (Cspg2)], 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. Fbln2 expression was the most affected, and the reduction in menin-null MEFs for Fbln2, Postn, and Cspg2 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. Postn and Cspg2 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 Men1-null mouse embryos.

Original languageEnglish (US)
Pages (from-to)1041-1051
Number of pages11
JournalMolecular Cancer Research
Volume5
Issue number10
DOIs
StatePublished - Oct 1 2007

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ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Ji, Y., Prasad, N. B., Novotny, E. A., Kaur, S., Elkahloun, A., Chen, Y., Zhang, R. Z., Chu, M. L., Agarwal, S. K., Marx, S. J., Collins, F. S., & Chandrasekharappa, S. C. (2007). Mouse embryo fibroblasts lacking the tumor suppressor menin show altered expression of extracellular matrix protein genes. Molecular Cancer Research, 5(10), 1041-1051. https://doi.org/10.1158/1541-7786.MCR-06-0379