Cancer Letters

Cancer Letters

Volume 189, Issue 1, 10 January 2003, Pages 1-10
Cancer Letters

Mini-review
Menin interacting proteins as clues toward the understanding of multiple endocrine neoplasia type 1

https://doi.org/10.1016/S0304-3835(02)00509-8Get rights and content

Abstract

Multiple endocrine neoplasia type 1 (MEN1) is a familial cancer syndrome characterized mostly by tumors of the parathyroids, pancreas and anterior pituitary. The gene responsible, MEN1, encodes Menin, a 610 aminoacid nuclear protein with no sequence homology to other proteins. Although a mouse knock-out model is available, the function of Menin is still elusive. Proteins of known function are shown to interact with Menin: JunD, nuclear factor-KappaB, Smad3, Pem, Nm23H1, glial fibrillary acidic protein, Vimentin, and probably P53. Their partnership with Menin may correspond to a regulation of their activity, but their relevance to the various traits of MEN1 pathogenicity is not established. This raises fundamental issues on the regulation pathways implicated in this complex endocrine disease.

Section snippets

MEN1, a complex genetic disease predisposing to endocrine tumors

Multiple Endocrine Neoplasia type 1 (MEN1, Online Mendelian Inheritance in Men (OMIM) 131100) is a cancer predisposition syndrome inherited as a dominant trait. It affects a variety of endocrine tissues, in particular parathyroids, endocrine pancreas, anterior pituitary, foregut-derived neuroendocrine tissues and adrenal cortex. Other tissues are affected in MEN1 patients, albeit less frequently: cutaneous proliferations such as angiofibroma, collagenoma, lipoma or melanoma, and peripheral or

Menin and the regulation of transcription

In the last 3 years, Menin has been shown to interact with several proteins of known function. It is striking that the first four protein partners (MIPs, for Menin Interacting Proteins) of Menin which have been unraveled are known for their central role in the regulation of transcription.

The prototype is JunD, a transcription factor belonging to the AP1 transcription complex family. Identified by the yeast two-hybrid method, the Menin–JunD interaction has been established by several other

Menin and intermediate filaments

Although Menin has been reported primarily as a nuclear protein [25], several reports have brought trustworthy indications that it may be present also in the cytoplasm [8], [26], [27]. However, there is, to our knowledge, no definite proof that a nuclear/cytoplasmic balance of Menin could be regulated during the cell cycle [27]. In this respect, it is striking that the protein glial fibrillary acidic protein (GFAP) has been recovered from a yeast two-hybrid screen of a human adult brain cDNA

Menin and the control of genome stability

The binding of Menin to Nm23H1 might be relevant also to the control of genomic stability as isoform 1 of the rat Nm23 (and not isoform 2) is associated to the centrosomes of interphase C6 glial cells [36]. The role of centrosomes in the maintenance of chromosome integrity is well documented, while they also orchestrate the formation of GFAP and Vimentin containing filaments through protein phosphorylations regulated by GTPases.

This is of particular interest since a role of Menin (either

Conclusion

Consistent with the fact that MEN1 represents a complex syndrome with –at the same time- a strict tissue specificity and a relatively broad spectrum of both associated tumors and phenotype expressivity, the presently known protein partners of Menin seem to drive it through various cellular compartments to act in different regulation pathways. In this respect, they have provided information that will turn out to be essential in the understanding of the pathogenicity of MEN1. However, at the

Acknowledgements

This article has been made possible after the June 2002 workshop on Multiple Endocrine Neoplasia organized in Grand Rapids, Mi, by Bin T. Teh. Our special tanks go to Anders Gobl and Naganari Ohkura who have made their results available to us prior to publication. A.P. is the recipient of an allocation de recherche from the French Ministry of Research and Technology, and B.Z. was supported by a stipend from CNRS. This work was funded by the Association pour la Recherche sur le Cancer (grant No.

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