Dataset Information

Impaired transforming growth factor-? (TGF-?) transcriptional activity and cell proliferation control of a menin in-frame deletion mutant associated with multiple endocrine neoplasia type 1 (MEN1).

ABSTRACT: Multiple endocrine neoplasia type 1 (MEN1) is characterized by tumors of the parathyroid, enteropancreas, and anterior pituitary. The MEN1 gene encodes the tumor suppressor menin of 610 amino acids that has multiple protein partners and activities. The particular pathways that, when lost, lead to tumorigenesis are not known. We demonstrated that members of a three-generation MEN1 kindred are heterozygous for a donor splice site mutation at the beginning of intron 3 (IVS3 + 1G?A). Lymphoblastoid cells of a mutant gene carrier had, in addition to the wild-type menin transcript, an aberrant transcript resulting from use of a cryptic splice site within exon III that splices to the start of exon IV. The predicted menin ?(184-218) mutant has an in-frame deletion of 35 amino acids but is otherwise of wild-type sequence. The transfected menin ?(184-218) mutant was well expressed and fully able to mediate the normal inhibition of the activity of the transcriptional regulators JunD and NF-?B. However, it was defective in mediating TGF-?-stimulated Smad3 action in promoter-reporter assays in insulinoma cells. Importantly, lymphoblastoid cells from an individual heterozygous for the mutation had reduced TGF-?-induced (Smad3) transcriptional activity but normal JunD and NF-?B function. In addition, the mutant gene carrier lymphoblastoid cells proliferated faster and were less responsive to the cytostatic effects of TGF-? than cells from an unaffected family member. In conclusion, the menin mutant exhibits selective loss of the TGF-? signaling pathway and loss of cell proliferation control contributing to the development of MEN1.

SUBMITTER: Canaff L

PROVIDER: S-EPMC3318699 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Impaired transforming growth factor-β (TGF-β) transcriptional activity and cell proliferation control of a menin in-frame deletion mutant associated with multiple endocrine neoplasia type 1 (MEN1).

Canaff Lucie L Vanbellinghen Jean-François JF Kaji Hiroshi H Goltzman David D Hendy Geoffrey N GN

The Journal of biological chemistry 20120124 11

Multiple endocrine neoplasia type 1 (MEN1) is characterized by tumors of the parathyroid, enteropancreas, and anterior pituitary. The MEN1 gene encodes the tumor suppressor menin of 610 amino acids that has multiple protein partners and activities. The particular pathways that, when lost, lead to tumorigenesis are not known. We demonstrated that members of a three-generation MEN1 kindred are heterozygous for a donor splice site mutation at the beginning of intron 3 (IVS3 + 1G→A). Lymphoblastoid ...[more]

PMID: 22275377

Similar Datasets

Project description:Multiple endocrine neoplasia (MEN) is characterized by the occurrence of tumors involving two or more endocrine glands within a single patient. Four major forms of MEN, which are autosomal dominant disorders, are recognized and referred to as: MEN type 1 (MEN1), due to menin mutations; MEN2 (previously MEN2A) due to mutations of a tyrosine kinase receptor encoded by the rearranged during transfection (RET) protoncogene; MEN3 (previously MEN2B) due to RET mutations; and MEN4 due to cyclin-dependent kinase inhibitor (CDNK1B) mutations. Each MEN type is associated with the occurrence of specific tumors. Thus, MEN1 is characterized by the occurrence of parathyroid, pancreatic islet and anterior pituitary tumors; MEN2 is characterized by the occurrence of medullary thyroid carcinoma (MTC) in association with phaeochromocytoma and parathyroid tumors; MEN3 is characterized by the occurrence of MTC and phaeochromocytoma in association with a marfanoid habitus, mucosal neuromas, medullated corneal fibers and intestinal autonomic ganglion dysfunction, leading to megacolon; and MEN4, which is also referred to as MENX, is characterized by the occurrence of parathyroid and anterior pituitary tumors in possible association with tumors of the adrenals, kidneys, and reproductive organs. This review will focus on the clinical and molecular details of the MEN1 and MEN4 syndromes. The gene causing MEN1 is located on chromosome 11q13, and encodes a 610 amino-acid protein, menin, which has functions in cell division, genome stability, and transcription regulation. Menin, which acts as scaffold protein, may increase or decrease gene expression by epigenetic regulation of gene expression via histone methylation. Thus, menin by forming a subunit of the mixed lineage leukemia (MLL) complexes that trimethylate histone H3 at lysine 4 (H3K4), facilitates activation of transcriptional activity in target genes such as cyclin-dependent kinase (CDK) inhibitors; and by interacting with the suppressor of variegation 3-9 homolog family protein (SUV39H1) to mediate H3K methylation, thereby silencing transcriptional activity of target genes. MEN1-associated tumors harbor germline and somatic mutations, consistent with Knudson's two-hit hypothesis. Genetic diagnosis to identify individuals with germline MEN1 mutations has facilitated appropriate targeting of clinical, biochemical and radiological screening for this high risk group of patients for whom earlier implementation of treatments can then be considered. MEN4 is caused by heterozygous mutations of CDNK1B which encodes the 196 amino-acid CDK1 p27Kip1, which is activated by H3K4 methylation.

Dataset Information

Impaired transforming growth factor-? (TGF-?) transcriptional activity and cell proliferation control of a menin in-frame deletion mutant associated with multiple endocrine neoplasia type 1 (MEN1).

Publications

Impaired transforming growth factor-β (TGF-β) transcriptional activity and cell proliferation control of a menin in-frame deletion mutant associated with multiple endocrine neoplasia type 1 (MEN1).

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets