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Menin induces endodermal differentiation in aggregated P19 stem cells by modulating the retinoic acid receptors

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Abstract

Menin, a ubiquitously expressed protein, is the product of the multiple endocrine neoplasia type I (Men1) gene, mutations of which cause tumors primarily of the parathyroid, endocrine pancreas, and anterior pituitary. Menin-null mice display early embryonic lethality, and thus imply a critical role for menin in early development. In this study, using the P19 embryonic carcinoma stem cells, we studied menin’s role in cell differentiation. Menin expression is induced in P19 cell aggregates by retinoic acid (RA). Menin over-expressing stable clones proliferated in a significantly reduced rate compared to the empty vector harboring cells. RA induced cell death in aggregated menin over-expressing cells. However, in the absence of RA, specific populations of the aggregated menin over-expressing cells displayed the characteristic of an endodermal phenotype by the acquisition of cytokeratin Endo A expression (TROMA-1), a marker for the primitive endoderm, with a concomitant loss of the stem cell marker SSEA-1. Menin’s ability to induce endodermal differentiation in specific populations of the aggregated cells in the absence of RA implied that menin could substitute RA by inducing a set of target genes that are RA responsive. Menin over-expressing cells upon aggregation showed a robust expression of RA receptors (RAR), RARα, β, and γ relative to the empty vector-harboring cells. Moreover, endodermal differentiation was inhibited by the pan-RAR antagonist Ro41-5253, suggesting that menin could induce endodermal differentiation of uncommitted cells by functionally modulating the RARs.

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Acknowledgments

This study was supported by Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, USA.

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Authors and Affiliations

  1. Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, 50 South Dr, Bldg 50, Room 5232, Bethesda, MD, 20892, USA

    Jyotshnabala Kanungo & Settara C. Chandrasekharappa

  2. Division of Neurotoxicology, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Road, Bldg 53D, Rm 203O, Jefferson, AR, 72079, USA

    Jyotshnabala Kanungo

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  1. Jyotshnabala Kanungo
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Correspondence to Jyotshnabala Kanungo or Settara C. Chandrasekharappa.

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Kanungo, J., Chandrasekharappa, S.C. Menin induces endodermal differentiation in aggregated P19 stem cells by modulating the retinoic acid receptors. Mol Cell Biochem 359, 95–104 (2012). https://doi.org/10.1007/s11010-011-1003-2

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