The cellular function of the menin tumor suppressor protein, product of the MEN1 gene mutated in familial multiple endocrine neoplasia type 1, has not been defined. We now show that menin is associated with a histone methyltransferase complex containing two trithorax family proteins, MLL2 and Ash2L, and other homologs of the yeast Set1 assembly. This menin-associated complex methylates histone H3 on lysine 4. A subset of tumor-derived menin mutants lacks the associated histone methyltransferase activity. In addition, menin is associated with RNA polymerase II whose large subunit carboxyl-terminal domain is phosphorylated on Ser 5. Men1 knockout embryos and cells show decreased expression of the homeobox genes Hoxc6 and Hoxc8. Chromatin immunoprecipitation experiments reveal that menin is bound to the Hoxc8 locus. These results suggest that menin activates the transcription of differentiation-regulating genes by covalent histone modification, and that this activity is related to tumor suppression by MEN1.
Multiple endocrine neoplasia type 1 (MEN1) is an inherited cancer predisposition syndrome typified by development of tumors in parathyroid, pituitary and endocrine pancreas, as well as less common sites including both endocrine and nonendocrine organs. Deletion or mutation of the tumor suppressor gene MEN1 on chromosome 11 has been identified in many cases of MEN1 as well as in sporadic tumors. The molecular biology of menin, the protein encoded by MEN1, remains poorly understood. Here we describe a mouse model of MEN1 in which tumors were seen in pancreatic islets, pituitary, thyroid and parathyroid, adrenal glands, testes and ovaries. The observed tumor spectrum therefore includes types commonly seen in MEN1 patients and additional types. Pancreatic pathology was most common, evident in over 80% of animals, while other tumor types developed with lower frequency and generally later onset. Tumors of multiple endocrine organs were observed frequently, but progression to carcinoma and metastasis were not evident. Tumors in all sites showed loss of heterozygosity at the Men1 locus, though the frequency in testicular tumors was only 36%, indicating that a different molecular mechanism of tumorigenesis occurs in those Leydig tumors that do not show loss of the normal Men1 allele. Menin expression was below the level of detection in ovary, thyroid and testis, but loss of nuclear menin immunoreactivity was observed uniformly in all pancreatic islet adenomas and in some hyperplastic islet cells, suggesting that complete loss of Men1 is a critical point in islet tumor progression in this model. ' 2006 Wiley-Liss, Inc.Key words: endocrine; pancreas; pituitary; parathyroid; testis; ovary Multiple endocrine neoplasia type 1 (MEN1) in humans is a rare cancer predisposition syndrome that results in adult onset tumorigenesis in endocrine tissues, predominantly the parathyroid, anterior pituitary and pancreatic islets of Langerhans. Tumors of the adrenal glands, bronchial and foregut carcinoids, lipomas and fibromas are also observed in the MEN1 tumor spectrum (for review see Ref. 1 and OMIM 131100). Familial MEN1 is inherited as an autosomal dominant trait. Linkage mapping in familial MEN1 led to the identification of a tumor suppressor gene on 11q13. 2 Mutations of this gene, MEN1, are observed in both familial and de novo cases of MEN1, and additionally in some sporadic cases of the individual tumor types seen in MEN1. [3][4][5][6][7][8][9] MEN1 encodes a protein, designated menin, that does not show significant homology to any known protein family. Menin has been shown to be widely expressed and present as an intracellular, predominantly nuclear, protein. 10,11 Recent evidence has suggested that interaction with histone methyltransferase complexes 12,13 and with histone deacetylase activity 14,15 is important for menin's activity as a transcriptional co-regulator associated with the MLL complex 16 and with JunD 17 respectively. While several menin-interacting partners have been identified, 16,18-21 the molecular mechanism ...
Mutations of the MEN1 gene, encoding the tumor suppressor menin, predispose individuals to the cancer syndrome multiple endocrine neoplasia type 1, characterized by the development of tumors of the endocrine pancreas and anterior pituitary and parathyroid glands. We have targeted the murine Men1 gene by using Cre recombinase-loxP technology to develop both total and tissue-specific knockouts of the gene. Conditional homozygous inactivation of the Men1 gene in the pituitary gland and endocrine pancreas bypasses the embryonic lethality associated with a constitutional Men1 ؊/؊ genotype and leads to -cell hyperplasia in less than 4 months and insulinomas and prolactinomas starting at 9 months. The pituitary gland and pancreas develop normally in the conditional absence of menin, but loss of this transcriptional cofactor is sufficient to cause -cell hyperplasia in some islets; however, such loss is not sufficient to initiate pituitary gland tumorigenesis, suggesting that additional genetic events are necessary for the latter.
DnA damage and the elicited cellular response underlie the etiology of tumorigenesis and ageing. Yet, how this response integrates inputs from cells' environmental cues remains underexplored. Here we report that the BmP-smad1 pathway, which is essential for embryonic development and tissue homeostasis, has an important role in the DnA damage response and oncogenesis. on genotoxic stress, Atm phosphorylates BmPs-activated smad1 in the nucleus on s239, which disrupts smad1 interaction with protein phosphatase PPm1A, leading to enhanced activation and upregulation of smad1. smad1 then interacts with p53 and inhibits mdm2-mediated p53 ubiquitination and degradation to regulate cell proliferation and survival. Enhanced smad1 s239 phosphorylation, and Smad1 mutations causing s239 substitution were detected in oesophageal and gastric cancer samples, respectively. These findings suggest that BmP-smad1 signalling participates in the DnA damage response via the Atm-p53 pathway, thus providing a molecular mechanism whereby BmP-smad1 loss-of-function leads to tumorigenesis, for example, juvenile polyposis and Cowden syndromes.
Background: Smad4 mutant embryos arrest shortly after implantation and display a characteristic shortened proximodistal axis, a significantly reduced epiblast, as well as a thickened visceral endoderm layer. Conditional rescue experiments demonstrate that bypassing the primary requirement for Smad4 in the extra-embryonic endoderm allows the epiblast to gastrulate. Smad4-independent TGF-β signals are thus sufficient to promote mesoderm formation and patterning. To further analyse essential Smad4 activities contributed by the extra-embryonic tissues, and characterise Smad4 dependent pathways in the early embryo, here we performed transcriptional profiling of Smad4 null embryonic stem (ES) cells and day 4 embryoid bodies (EBs).
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