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.
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.
Hussein
Nader
N
Université Claude Bernard Lyon, Lyon, France.
Lu
JieLi
J
Casse
Huguette
H
Fontanière
Sandra
S
Morera
Anne-Marie
AM
Guittot
Séverine Mazaud
SM
Calender
Alain
A
Di Clemente
Nathalie
N
Zhang
Chang X
CX
D000818:Animals; D054304:Anti-Mullerian Hormone / Q000378:metabolism*; D015152:Blotting, Northern; D015153:Blotting, Western; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D006579:Heterozygote; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D007984:Leydig Cell Tumor / Q000378:metabolism* / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018761:Multiple Endocrine Neoplasia Type 1 / Q000378:metabolism* / Q000473:pathology; D010957:Plasmids; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018000:Receptors, Peptide / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D019485:Bone Morphogenetic Proteins; D050763:Cyclin-Dependent Kinase Inhibitor p18; C484898:Men1 protein, mouse; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D018000:Receptors, Peptide; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C084621:anti-Mullerian hormone receptor; D050760:Cyclin-Dependent Kinase Inhibitor p27; D054304:Anti-Mullerian Hormone; D008156:Luciferases