Deregulation of anti-Mullerian hormone/BMP and transforming growth factor-{beta} pathways in Leydig cell lesions developed in male heterozygous multiple endocrine Neoplasia type 1 mutant mice

Nader Hussein (1) , Jieli Lu (1) , Huguette Casse (1) , Sandra Fontanière (1, 1, 2) , Anne-Marie Morera (3) , Séverine Mazaud Guittot (3) , Alain Calender (1, 4, 5) , Nathalie Di Clemente (6) , Chang Xian Zhang (1, 7)

1 GMSC - Génétique moléculaire, signalisation et cancer
2 IACR - International Agency for Cancer Research
3 CCD - Communications Cellulaires et Différenciation
4 UCBL - Université Claude Bernard Lyon 1
5 Service de Génétique Moléculaire et Clinique
6 Endocrinologie et Génétique de la Reproduction et du Développement
7 The E-Institute of Shanghai

Multiple endocrine neoplasia type 1 (MEN1) results from the mutation of the predisposing gene, MEN1. Heterozygous Men1 mutant mice previously generated by several laboratories, including ours, mimic largely MEN1 pathology. Interestingly, our heterozygous Men1 mutant mice exhibit not only the endocrine tumours commonly seen in MEN1 patients, but also Leydig cell tumours (LCT) with high frequency, accompanied systematically by loss of the wild-type Men1 allele. As there exists a similarity of tumour phenotype between these mice and those mutated for the components of anti-Mullerian hormone (AMH)/bone morphogenic protein (BMP) pathway belonging to transforming growth factor-beta (TGF-beta) family, we investigated the expression and the activity of this pathway, known to have an important biological role in Leydig cells. Here, we report that the expression of AMH receptor type 2 is reduced in Men1 LCTs. Both immunostaining and western blot analyses also demonstrate a markedly decreased nuclear expression of Smad1, 3, 4 and 5 in the tumours. More interestingly, we show that the reconstituted menin expression in Men1-deficient Leydig cells derived from LCTs can significantly increase the transcriptional activity of a BMP pathway target promoter, XVent2. Furthermore, we found that the expression of p18, p27 and cyclin dependant kinase 4 (Cdk4), targets of TGF-beta pathways, is altered in the Leydig cell lesions. Our data provide the evidence of the deregulation of AMH/BMP and TGF-beta pathways in mouse Men1 LCTs, highlighting their involvement in tumorigenesis of Leydig cells due to Men1 inactivation.

Mots clés: Animals; Anti-Mullerian Hormone/metabolism; Blotting; Northern; Western; Bone Morphogenetic Proteins/metabolism; Cyclin-Dependent Kinase Inhibitor p18/metabolism; Cyclin-Dependent Kinase Inhibitor p27/metabolism; Heterozygote; Leydig Cell Tumor/metabolism; Leydig Cell Tumor/pathology; Luciferases/metabolism; Mice; Knockout; Multiple Endocrine Neoplasia Type 1/metabolism; Multiple Endocrine Neoplasia Type 1/pathology; Plasmids; Proto-Oncogene Proteins/metabolism; RNA; Transforming Growth Factor beta/metabolism; Reverse Transcriptase Polymerase Chain Reaction; Smad Proteins/metabolism

Mots clés: Immunoenzyme Techniques; Immunoprecipitation; Male; Messenger/genetics; Messenger/metabolism; Receptors; Peptide/metabolism

Domaines: Endocrinologie et métabolisme

Nader Hussein, Jieli Lu, Huguette Casse, Sandra Fontanière, Anne-Marie Morera, et al.. Deregulation of anti-Mullerian hormone/BMP and transforming growth factor-{beta} pathways in Leydig cell lesions developed in male heterozygous multiple endocrine Neoplasia type 1 mutant mice. Endocrine-Related Cancer, 2008, 15 (1), pp. 217-27. ⟨10.1677/ERC-06-0046⟩. ⟨hal-00671020⟩