MEN1
Menin [SCG2]
Publications[править]
Mutations of the MEN1 gene predispose to multiple endocrine neoplasia type 1 (MEN1) syndrome. Our group and others have shown that Men1 disruption in mice recapitulates MEN1 pathology. Intriguingly, rare lesions in hormone-dependent tissues, such as prostate and mammary glands, were also observed in the Men1 mutant mice. To study the occurrence of prostate lesions, we followed a male mouse cohort of 47 Men1 /- mice and 23 age-matched control littermates, starting at 18 months of age, and analysed the prostate glands from the cohort. Six Men1 /- mice (12.8%) developed prostate cancer, including two adenocarcinomas and four in situ carcinomas, while none of the control mice developed cancerous lesions. The expression of menin encoded by the Men1 gene was found to be drastically reduced in all carcinomas, and partial LOH of the wild-type Men1 allele was detected in three of the five analysed lesions. Using immunostaining for the androgen receptor and p63, a basal epithelial cell marker, we demonstrated that the menin-negative prostate cancer cells did not display p63 expression and that the androgen receptor was expressed but more heterogeneous in these lesions. Furthermore, our data showed that the expression of the cyclin-dependent kinase inhibitor CDKN1B (p27), a Men1 target gene known to be inactivated during prostate cell tumorigenesis, was notably decreased in the prostate cancers that developed in the mutant mice. Our work suggests the possible involvement of Men1 inactivation in the tumorigenesis of the prostate gland.
MeSH Terms
- Adenocarcinoma
- Aging
- Animals
- Blotting, Southern
- Cyclin-Dependent Kinase Inhibitor p27
- Heterozygote
- Immunoenzyme Techniques
- Loss of Heterozygosity
- Male
- Mice
- Mice, Inbred C57BL
- Phosphoproteins
- Prostatic Neoplasms
- Proto-Oncogene Proteins
- Receptors, Androgen
- Trans-Activators
In multiple endocrine neoplasia type 1 (MEN1), age-related tumour penetrance according to the type of MEN1 germline mutation has not been investigated in-depth. This study was conducted to examine whether carriers of out-of-frame/truncating and in-frame MEN1 mutations differ in age-related tumour penetrance. A multicentre study with biochemical, hormonal and radiological screening for MEN1-associated tumours. A total of 258 MEN1 carriers from six major German tertiary referral centres averaging 43 years of age at last follow-up. Main outcome measure was time to first diagnosis of MEN1-associated tumours. Independent of the year of birth and observation period, time to first tumour diagnosis did not vary much by the type of MEN1 germline mutation or endocrine organ system, and perhaps not even by the type of endocrine tumour when the amount of time was considered by which the diagnosis probably has been advanced through the manifestation of hormonal symptoms. Parathyroid hyperplasia and adenomas developed almost twice as often as enteropancreatic and pituitary tumours (77%vs. 49-32%), and more than five to sevenfold as often as adrenal cortical tumours and carcinoids (77%vs. 15-10%), reaching penetrance rates of up to 90%, 60%, 40%, 26% and 17%, respectively. The heterogeneity of tumour penetrance was marked, ranging from 9 years to 25 years for the earliest, and from 68 years to 77 years for the latest tumour manifestation. Because of our inability of predicting tumour penetrance and malignant transformation individually, life-long follow-up of MEN1 carriers is warranted to prevent tumour morbidity.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aging
- Analysis of Variance
- Child
- Female
- Germ-Line Mutation
- Heterozygote
- Humans
- Male
- Middle Aged
- Multiple Endocrine Neoplasia Type 1
- Penetrance
We describe the isolation and expression of a murine homologue of the Phospholipase C beta3 Neighboring Gene (PNG), located in the MEN1 region on chromosome 11q13. The PNG cDNA was isolated using a human PNG cDNA clone (SOM172). Human and mouse PNG do not have any marked similarity to other known genes on the DNA level, but the predicted protein display similarity to the C-terminal part of Phospholipase C beta2. Northern blots with mouse PNG probes revealed expression of a 1 kb message in multiple tissues, and an additional 2.3 kb band in testis. The predicted murine protein contains 203 amino acids. In situ hybridization histochemistry displayed png mRNA expression in several tissues of the midstage mouse embryo, including the central nervous system. In late stage embryos, png was highly expressed in skeletal muscle, retina and neocortex. In the adult animal, expression was restricted to testis and thymus.
MeSH Terms
- Aging
- Amino Acid Sequence
- Animals
- Animals, Newborn
- Base Sequence
- Brain
- Chromosome Mapping
- Humans
- In Situ Hybridization
- Isoenzymes
- Male
- Mice
- Molecular Sequence Data
- Oligonucleotide Probes
- Organ Specificity
- Phospholipase C beta
- Protein Biosynthesis
- Protein Phosphatase 1
- Proteins
- RNA, Messenger
- Sequence Homology, Amino Acid
- Transcription, Genetic
- Type C Phospholipases