Biomedical subjects

Philippe Bertolino

Publications and source records attributed to Philippe Bertolino.

7 recordsLinked to original sources

PubMed2006

Reconstituted expression of menin in Men1-deficient mouse Leydig tumour cells induces cell cycle arrest and apoptosis.

Multiple endocrine neoplasia type 1 (MEN1) is a hereditary syndrome caused by the inactivation of the responsible gene, MEN1. To date, the lack of MEN1-deficient cell lines derived directly from MEN1 tumours has hampered the detailed study of the MEN1 gene. We have established several stable Men1-deficient Leydig cell tumour (LCT) lines derived from a Leydig cell tumour developed in a male heterozygous Men1 mutant mouse. Our data show that these cell lines maintain the basic characteristics of Leydig cells in terms of both androgen synthesis and gene expression. Interestingly, reconstituted menin expression in one of Men1-deficient LCT cell lines resulted in cell growth inhibition, suggesting that the function of cell growth suppression of the menin pathway, apart from menin itself, is essentially preserved in these cells. Furthermore, we show that menin re-expression in these Men1-deficient cells leads to a block in the transition from G0/G1 to S phase of the cell cycle and an increase in apoptosis, accompanied by a marked increase of p18INK4C and p27Kip1 expression. The current study therefore highlights the importance of menin expression in cell cycle and cell survival control in endocrine cells, and may provide insights into the mechanisms of tumour suppression by menin in related endocrine tumours.

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PubMed2006

Analysis of p27(Kip1) expression in insulinomas developed in pancreatic beta-cell specific Men1 mutant mice.

Multiple Endocrine Neoplasia type 1 (MEN1) is a hereditary disease characterised by the occurrence of multiple endocrine tumours. The biological functions of the responsible gene, MEN1, and its encoded protein, menin, remain so far largely elusive. The recent generation of Men1 mutant mice by our group and other laboratories provides powerful tools allowing for the identification of cellular and molecular events that occur after gene disruption. Interestingly, it has been recently reported that p27(Kip1) expression is regulated by menin and that decreased p27(Kip1) expression can be found in MEN1 insulinomas and parathyroid adenomas. In order to address whether and when p27(Kip1) expression alters during insulinoma development in pancreatic beta-cell-specific Men1 mutant mice, we analysed p27(Kip1) expression in islet lesions from mutant mice at different ages. Our data revealed that p27(Kip1) protein expression was reduced in 40 out of 52 (77%) insulinomas analysed, whereas the remaining 12 insulinomas (23%) did not show altered p27(Kip1) expression. No difference between the insulinomas with and without decreased p27(Kip1) expression could be observed in terms of histological features or menin inactivation. Furthermore, our analysis on hyperplastic and dysplastic islets developed in young mutant mice showed the lack of detectable alteration in p27(Kip1) expression, despite evident loss of menin expression in a substantial proportion of islet cells. Our work confirms the altered p27(Kip1) expression reported in tumours from MEN1 patients, whereas it suggests that other molecular events may also participate in the tumorigenesis process initiated by the Men1 gene inactivation.

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PubMed2005

TGF-beta receptor function in the endothelium.

Genetic studies in mice and humans have revealed the pivotal role of transforming growth factor-beta (TGF-beta) signaling during angiogenesis. Mice deficient for various TGF-beta signaling components present an embryonic lethality due to vascular defects. In patients, mutations in the TGF-beta type I receptor ALK1 or in the accessory TGF-beta receptor endoglin are linked to an autosomal dominant disorder of vascular dysplasia termed Hereditary Haemorrhagic Telangiectasia (HHT). It has puzzled researchers for years to explain the effects of TGF-beta being a stimulator and an inhibitor of angiogenesis in vitro and in vivo. Recently, a model has been proposed in which TGF-beta by binding to the TGF-beta type II receptor can activate two distinct type I receptors in endothelial cells (ECs), i.e., the EC-restricted ALK1 and the broadly expressed ALK-5, which have opposite effects on ECs behavior. ALK1 via Smad1/5 transcription factors stimulates EC proliferation and migration, whereas ALK5 via Smad2/3 inhibits EC proliferation and migration. Here, the new findings are presented concerning the molecular mechanisms that take place in ECs to precisely regulate and even switch between TGF-beta-induced biological responses. In particular, the role of the accessory TGF-beta receptor endoglin in the regulation of EC behavior is addressed and new insights are discussed concerning the possible mechanisms that are implicated in the development of HHT.

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PubMed2005

Transforming growth factor-beta signal transduction in angiogenesis and vascular disorders.

Transforming growth factor (TGF)-beta is a multifunctional protein that initiates its diverse cellular responses by binding to and activating specific type I and type II serine/threonine kinase receptors. TGF-beta can act as a regulator of proliferation, migration, survival, differentiation, and extracellular matrix synthesis in endothelial cells and vascular smooth muscle cells, as well as in the maintenance of vascular homeostasis. Importantly, genetic studies in humans have revealed the pivotal role of TGF-beta as well as its signaling components in angiogenesis. Mutations in two TGF-beta receptors (ie, the activin receptor-like kinase (ALK) 1 and the accessory TGF-beta receptor endoglin) have been linked to vascular disorders named hereditary hemorrhagic telangiectasia. In addition, knockout mice for the different components of the TGF-beta signaling pathway have shown that TGF-beta is indispensable for angiogenesis. Recent studies have revealed that TGF-beta can regulate vascular homeostasis by balancing the signaling between two distinct TGF-beta type I receptors (ie, the endothelial-restricted ALK1 and the broadly expressed ALK5 receptors). The activation of these receptors has been shown to induce opposite effects on endothelial cell behavior and angiogenesis. In this review, we will present recent advances in understanding the role of TGF-beta signaling in endothelial cells as well as the underlying molecular mechanisms by which perturbation of this pathway can lead to vascular disorders.

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PubMed2003

Pancreatic beta-cell-specific ablation of the multiple endocrine neoplasia type 1 (MEN1) gene causes full penetrance of insulinoma development in mice.

The function of the predisposition gene to multiple endocrine neoplasia type 1 (MEN1) syndrome remains largely unknown. Previous studies demonstrated that null mutation of the Men1 gene caused mid-gestation lethality in mice, whereas heterozygous Men1 knockout mice developed multiple endocrine tumors late in life. To seek direct evidence on the causal role of menin in suppressing tumor development, we generated mice in which the Men1 gene was disrupted specifically in pancreatic beta cells. These mice began to develop hyperplastic islets at as early as 2 months of age and insulinomas at 6 months of age. The islet lesions exhibited features of multistage tumor progression, including beta-cell dedifferentiation, angiogenesis, and altered expression of both E-cadherin and beta-catenin. Additionally, disturbance of blood insulin and glucose levels correlated with tumor development, mimicking human MEN1 symptoms. Our data indicate that this strain of mice provides a powerful tool for the study of the mechanisms of tumorigenesis related to MEN1 disease.

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PubMed2003

Heterozygous Men1 mutant mice develop a range of endocrine tumors mimicking multiple endocrine neoplasia type 1.

Multiple endocrine neoplasia type 1 (MEN1) is a hereditary syndrome characterized by the occurrence of multiple endocrine tumors of the parathyroid, pancreas, and anterior pituitary in patients. To study tumorigenesis related to the MEN1 syndrome, we have generated Men1 knockout mice using the gene targeting approach. Heterozygous Men1 mutant mice developed the same range of major endocrine tumors as is seen in MEN1 patients, affecting the parathyroid, pancreatic islets, pituitary and adrenal glands, as well as the thyroid, and exhibiting multistage tumor progression with metastatic potential. In particular, extrapancreatic gastrinoma, pancreatic glucagonoma, and mixed hormone-producing tumors in islets were observed. In addition, there was a high incidence of gonadal tumors of endocrine origin, i.e. Leydig cell tumors, and ovary sex-cord stromal cell tumors in heterozygous Men1 mutant mice. Hormonal disturbance, such as abnormal PTH and insulin levels, was also observed in these mice. These tumors were associated with loss of heterozygosity of the wild-type Men1 allele, suggesting that menin is involved in suppressing the development of these endocrine tumors. All of these features are reminiscent of MEN1 symptoms in humans and establish heterozygous Men1 mutant mice as a suitable model for this disease.

Animals↗

PubMed2003

Genetic ablation of the tumor suppressor menin causes lethality at mid-gestation with defects in multiple organs.

Patients suffering from multiple endocrine neoplasia type 1 (MEN1) are predisposed to multiple endocrine tumors. The MEN1 gene product, menin, is expressed in many embryonic, as well as adult tissues, and interacts with several proteins in vitro and in vivo. However, the biological function of menin remains largely unknown. Here we show that disruption of the Men1 gene in mice causes embryonic lethality at E11.5-E13.5. The Men1 null mutant embryos appeared smaller in size, frequently with body haemorrhages and oedemas, and a substantial proportion of them showed disclosure of the neural tube. Histological analysis revealed an abnormal development of the nervous system and heart hypotrophy in some Men1 null embryos. Furthermore, Men1 null livers generally displayed an altered organization of the epithelial and hematopoietic compartments associated with enhanced apoptosis. Chimerism analysis of embryos generated by injection of Men1 null ES cells, showed that cells lacking menin do not seem to have a general cell-autonomous defect. However, primary Men1 null embryonic fibroblasts entered senescence earlier than their wild-type counterparts. Despite normal proliferation ability, Men1 null ES cells exhibited a deficiency to form embryoid bodies, suggesting an impaired differentiation capacity in these cells. The present study demonstrates that menin plays an important role in the embryonic development of multiple organs in addition to its proposed role in tumor suppression.

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