Key words: Multiple endocrine neoplasia type 1, MEN1, Menin, Regulation of transcription, Intermediate filaments, Genome stability, Protein interactions.

Abstract

Multiple endocrine neoplasia type 1 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, NF-KappaB, Smad3, Pem, Nm23H1, GFAP, 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.

MEN1, a complex genetic disease predisposing to endocrine tumors

Multiple Endocrine Neoplasia type 1 (MEN1, 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 central nervous system (eg ependymoma) (table 1). Most MEN1 tumors present as benign at initial diagnosis. Nevertheless, they are able to produce highly malignant clones upon secondary genetic alterations, eg related to deregulation of growth factor production or cell-to-cell adhesion processes (see [1], for a review).

The MEN1 gene, which is localized onto chromosome 11q13, was identified in 1997. It consists of 10 exons, spanning 9 kb of genomic sequence, and encoding a protein of 610 aminoacids (Menin) [2, 3]. Menin does not reveal homologies to any other known proteins. The only motifs which have been recognized in the Menin sequence are two leucine zippers, and two nuclear localization sequences (NLS) in the carboxyterminal part of the protein (Fig. 1).

Menin has orthologs not only in mouse and rat, but also in zebrafish and drosophila (98%, 97%, 75%, and 47% homology, respectively), but there is no homolog known in the yeast Saccharomyces cerevisae [4-6]. It is striking that the amino acid substitutions reported as disease-associated missense mutations are among the best conserved during evolution, calling for a fundamental role in biological processes.

More than 300 unique germline mutations have now been identified in MEN1 families. Somatic mutations have also been reported in sporadic tumors of the same endocrine panel, although at a relatively low frequency (20-30% in parathyroid or endocrine pancreas to less than 1% in pituitary and adrenocortical tumors). No genotype-phenotype correlations have been established so far [7]. Most germline mutations (70%) are said truncating mutations (nonsense and frameshift), although truncated proteins have seldom been observed if ever [8].

Tumors in MEN1 affected patients show somatic loss of the wild-type allele (loss of heterozygosity (LOH) at 11q13)[9]. This observation is consistent with the fact that MEN1 is a tumor suppressor gene with most pathogenic mutations corresponding to a loss of function. Like other tumor suppressor genes, MEN1 is likely to be involved in the maintenance of genome stability, thus raising the issue of the randomness of the “second hit” in the Knudson’s theory ([10], vide infra).

Recently, a mouse model of MEN1 was produced via inactivation of the mouse Men1 gene through homologous recombination (knock-out mice)[11]. Homozygous inactivation of the Men1 gene was lethal early during embryogenesis. Interestingly, Men1+/- heterozygotes develop mostly hyperplastic pancreatic islets and small tumors from 9 months of age. Other tumors were also observed in these mice, e.g. parathyroid hyperplasia and adenoma, pituitary adenoma, and adrenocortical carcinoma (table 1).

Beside what can be learnt from animal models, Menin’s function can be anticipated neither from its protein sequence nor from its mutation profile in MEN1 patients. Whatever its function could be, Menin is supposed to play a role in defined regulation pathways leading to the control of cell growth (MEN1 is primarily an hyperplastic syndrome) and/or the maintenance of genomic integrity. It is thus expected that deciphering the interaction network(s) in which Menin is implicated will enable us to tackle its biological role.

Menin and the regulation of transcription

In the last three 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 techniques (Table 2), and has been ascribed to specific domains of each protein (Fig. 1)[12]. Wild-type Menin represses transcriptional activation mediated by JunD, maybe via a histone deacetylase-dependent mechanism [12, 13]. It is not obvious to reconcile an antagonistic action of Menin towards JunD with its tumor suppressive function. Indeed, JunD has a reported effect in the inhibition of cell growth, a property which is unique from that of the other AP1 proteins. Menin, like JunD has a role in the suppression of RAS-induced tumorigenicity [14]. In addition, JunD-/- fibroblasts are hypersensisitve to UV light indicating that JunD acts as a pro-apoptotic factor in the P53 pathway [15]. It has been suggested that this paradoxical situation could be due to a differential binding of Menin interfering with the balance between the two known isoforms of JunD [16]. It remains that the ubiquitousness and the apparently constitutive expression of JunD, its puzzling role in oncogenesis, and the relatively mild (and non endocrine) phenotype of the JunD null mice (Table 3)[17], do not contribute to a better understanding of MEN1 pathogenicity.

Menin interacts directly with three members of the NF-KappaB family of transcription regulators, NF-KappaB1 (p50), NF-KappaB2 (p52), and RelA (p65) [18](Table 2). These proteins are known to play a central role in oncogenesis of various organs, as they modulate the expression of numerous genes as combination of homo and hetero-dimers [19]. They also present interesting features, such as their clustering in the cytoplasm by IB, and, upon mitogenic induction followed by phosphorylation and degradation of IB leading to the release of NF-KappaB, their migration to the nucleus. It is noteworthy that Menin represses NF-KappaB mediated transactivation since it does alike to JunD. It is also interesting to underline that NF-KappaB and JunD cooperate –and interact directly- to activate transcription in rat hepatocytes [20]. The phenotype of NF-KappaB knock-out mice has –a priori- little to see with MEN1, and it is more related to the functioning of the immune system. Only RelA-/- mice present with an apoptosis-related lethality (Table 3).

In a very elegant study performed in rat pituitary cells, Kaji et al. [21] have demonstrated that Menin interferes with the TGFß signaling pathway at the level of Smad3. Moreover, the authors have shown by co-immunoprecipitation of GH4C1 cell extracts, that Menin and Smad3 interact. However, they present no evidence of a direct binding of the two polypeptides, leaving open the possibility that the functional effect that they observe is mediated by the binding of other proteins and/or a signaling cascade (Table 2). In fact, there are many cross-talks between Smad-mediated TGFß signaling and the Ras phosphorylation pathway, leading, for instance, to activation of AP-1 complexes in which JunD and Fra2 are primary components [22]. Smad3 null mice present with a severe and complex phenotype in which endocrine tissues are not the major targets (Table 3). It remains that alterations of the TGFß signaling pathway is important in pancreatic carcinogenesis, as shown by the frequent inactivation of the downstream target Smad4. Moreover, the GTPase activity which has been shown recently to be an intrinsic biochemical function of Menin (vide infra) might represent a natural component of such a pathway. In this case, one would expect to discover other players in TGFß signalling being members of the MIP’s team, such as Activins which are known as important players in the mammalian endocrine reproductive axis [23].

Last in this series, the rodent protein Pem has been shown to bind Menin directly [24]. Pem is an homeobox-containing protein, expressed mostly in testis, which plays a role in the regulation of transcription. However, its direct relevance to MEN1 in humans is doubtful since its sequence has no known homolog in the human genome. Since mouse and human Menin are very similar, one could expect that a human protein with a function similar to that of Pem would bind Menin and thus play a role in the pathogenicity of MEN1 mutations. On the other hand, the existence of a mouse MIP which does not exist in human could be –in part- responsible for the differences observed between MEN1 and the only animal model available to date [11](Table 1).

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 library, using Menin as a bait [28]. As GFAP is part of type III intermediate filament (IF) in which Vimentin is a major player, the authors have also checked whether Menin could bind Vimentin. They confirmed Menin’s direct interaction with these two IF proteins both in vitro and in vivo. Hence, they suggest that the intermediate filament network interacts with, and may serve as a cytoplasmic sequestering network for Menin. This situation is reminiscent of that of wild-type p53 in glioblastomas where its cytoplasmic localization correlates with expression of vimentin and GFAP [29]. In the case of p53, cytoplasmic accumulation in tumor cells might indicate that the tumor suppressor is inactive with regard to its growth suppressive functions. Whether this is also the case for Menin remains to be established. In any case, the binding of Menin to GFAP raises the issue of a putative role of this tumor suppressor in glial cell oncogenesis. The potential association of ependymoma to the MEN1 syndromic pattern may be relevant to this issue (Table 1) [30].

The nucleoside diphosphate kinase ß isoform 1 which was first isolated as a metastasis suppressor under the name Nm23 [31], is also associated to GFAP-containing intermediate filaments in rat C6 glioma cells [32]. It is also one of the proteins which have been isolated in a yeast two-hybrid screen of a rat fetal forebrain cDNA library [33](Table 2). In this interaction, the Menin partner does not seem to regulate the known activities of Nm23H1. On the contrary, the latter enables Menin to hydrolyze GTP, hence linking Menin to Ras-related GTPases such as Rad. This exciting new result indicates that the Menin Interacting Protein approach is efficient in pointing to biochemical functions of the protein, like this atypical GTPase activity of Menin [34].

Van Kesteren et al. [35] have identified a molluscan Lymnaea stagnalis homolog to Menin whose postsynaptic expression is necessary to synapse formation between central neurons. Although the authors interprete their results in the light of the probable role of mammalian Menin in the regulation of transcription, one can wonder whether the Nm23H1-dependent GTPase activity of Menin associated to intermediate filaments would not be the major player in synapse plasticity instead.

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 directly or indirectly- has long been suspected in genome stability. Since there is no report indicating unambigously the existence of human MEN1 homozygotes (that can be understood from the lethal phenotype of homozygote Men1 knock-out mice), it is difficult to assimilate MEN1 to a chromosome instability syndrome, such as Fanconi anemia or ataxia telangiectasia [10]. Nevertheless, numerous reports have brought up converging evidence that normal cells from MEN1 patients present with an elevated level of chromosome alterations [37-42]. In addition, MEN1 tumos present with more genome aberrations than equivalent tumors from non-MEN1 patients [43]. MEN1 would not be an exception in this respect since most tumor suppressor genes involved in cancer predisposition are active at different levels in this process.

Beside the possible role of centrosomes, it is starting to be well-established that the key controls of genome stability include: i) the repair of double strand breaks, ii) the cell cycle checkpoints, and iii) the efficient elimination of damaged cells via apoptosis. A protein is known to play a central role in all these processes, P53, whose role in oncogenesis has long been documented. For this reason, we have checked whether Menin could bind P53, and we found that this was the case, both in vitro and in 293 HEK cells (Poisson, in preparation). The relevance of this observation to the actual MEN1 phenotype remains to be established.

Conclusion

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 informations that will turn out to be essential in the understanding of the pathogenicity of MEN1. However, at the present time, the picture remains puzzling (Fig. 2), and there is not definite clue as to the reason of the endocrine specificity of the affections. Could it be related to the interaction of Menin with other MIPs remaining to be discovered ?

Acknowledgments

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. AP is the recipient of an « allocation de recherche » from the french Ministry of Research and Technology, and BZ was supported by a stipend from CNRS. This work was funded by the Association pour la Recherche sur le Cancer (grant N° 4438).

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Table 1. Tumor types in MEN1

Table 2. Characteristics of Menin Interacting Proteins.

Table 3. Characteristics of mouse null mutants of Menin and Menin Interacting Proteins.

Figure 1. Mapping of Menin's interaction with its various partners.
The parts of the Menin sequence which have been implicated in the binding to different interacting proteins are indicated by colored solid bars under a schematic representation of the structure of Menin [2, 12, 18, 21, 24, 33, 34].

Figure 2. Tentative scheme of Menin’s interactions with its various partners.
Green arrows indicate positive regulation, while red lines suggest inhibitory effects. Menin is presented as a GTPase, the only biochemical activity that it is known to harbor to date [34]. However, it is not known which of Menin-GDP or Menin-GTP is the fraction of the protein active in a given pathway.

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