The neurofibromatosis-2 homologue, Merlin, and the tumor suppressor expanded function together in Drosophila to regulate cell proliferation and differentiation

Development ◽  
2000 ◽  
Vol 127 (6) ◽  
pp. 1315-1324 ◽  
Author(s):  
B.M. McCartney ◽  
R.M. Kulikauskas ◽  
D.R. LaJeunesse ◽  
R.G. Fehon
Keyword(s):  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Genetic Interaction ◽  
Suppressor Gene ◽  
Loss Of Function ◽  
Cortical Actin ◽  
Neurofibromatosis 2 ◽  
Protein 4.1 ◽  
Proliferation And Differentiation ◽  
Affected Tissue

Neurofibromatosis-2 is an inherited disorder characterized by the development of benign schwannomas and other Schwann-cell-derived tumors associated with the central nervous system. The Neurofibromatosis-2 tumor suppressor gene encodes Merlin, a member of the Protein 4.1 superfamily most closely related to Ezrin, Radixin and Moesin. This discovery suggested a novel function for Protein 4.1 family members in the regulation of cell proliferation; proteins in this family were previously thought to function primarily to link transmembrane proteins to underlying cortical actin. To understand the basic cellular functions of Merlin, we are investigating a Drosophila Neurofibromatosis-2 homologue, Merlin. Loss of Merlin function in Drosophila results in hyperplasia of the affected tissue without significant disruptions in differentiation. Similar phenotypes have been observed for mutations in another Protein 4.1 superfamily member in Drosophila, expanded. Because of the phenotypic and structural similarities between Merlin and expanded, we asked whether Merlin and Expanded function together to regulate cell proliferation. In this study, we demonstrate that recessive loss of function of either Merlin or expanded can dominantly enhance the phenotypes associated with mutations in the other. Consistent with this genetic interaction, we determined that Merlin and Expanded colocalize in Drosophila tissues and cells, and physically interact through a conserved N-terminal region of Expanded, characteristic of the Protein 4.1 family, and the C-terminal domain of Merlin. Loss of function of both Merlin and expanded in clones revealed that these proteins function to regulate differentiation in addition to proliferation in Drosophila. Further genetic analyses suggest a role for Merlin and Expanded specifically in Decapentaplegic-mediated differentiation events. These results indicate that Merlin and Expanded function together to regulate proliferation and differentiation, and have implications for understanding the functions of other Protein 4.1 superfamily members.

scholarly journals Distinct cellular and subcellular patterns of expression imply distinct functions for the Drosophila homologues of moesin and the neurofibromatosis 2 tumor suppressor, merlin.

1996 ◽  
Vol 133 (4) ◽  
pp. 843-852 ◽  
Author(s):  
B M McCartney ◽  
R G Fehon
Keyword(s):  
Tumor Suppressor ◽  
Cultured Cells ◽  
Transmembrane Proteins ◽  
Suppressor Gene ◽  
Cellular Functions ◽  
Neurofibromatosis 2 ◽  
Specific Antibodies ◽  
Protein 4.1 ◽  
Family Protein ◽  
Endocytic Compartments

Interest in members of the protein 4.1 super-family, which includes the ezrin-radixin-moesin (ERM) group, has been stimulated recently by the discovery that the human neurofibromatosis 2 (NF2) tumor suppressor gene encodes an ERM-like protein, merlin. Although many proteins in this family are thought to act by linking the actin-based cytoskeleton to transmembrane proteins, the cellular functions of merlin have not been defined. To investigate the cellular and developmental functions of these proteins, we have identified and characterized Drosophila homologues of moesin (Dmoesin) and of the NF2 tumor suppressor merlin (Dmerlin). Using specific antibodies, we show that although these proteins are frequently coexpressed in developing tissues, they display distinct subcellular localizations. While Dmoesin is observed in continuous association with the plasma membrane, as is typical for an ERM family protein, Dmerlin is found in punctuate structures at the membrane and in the cytoplasm. Investigation of Dmerlin cultured cells demonstrates that it is associated with endocytic compartments. As a result of these studies, we propose that the merlin protein has unique functions in the cell which differ from those of other ERM family members.

scholarly journals GIPC2 is an endocrine-specific tumor suppressor gene for both sporadic and hereditary tumors of RET- and SDHB-, but not VHL-associated clusters of pheochromocytoma/paraganglioma

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Yeqing Dong ◽  
Yongsheng Huang ◽  
Chengyan Fan ◽  
Liang Wang ◽  
Ran Zhang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Chromaffin Cells ◽  
Disease Free Survival ◽  
Suppressor Gene ◽  
Adrenal Chromaffin Cell ◽  
Putative Tumor Suppressor Gene ◽  
Mutant Effect ◽  
Hereditary Tumors

AbstractPheochromocytoma/paraganglioma (PPGL) is an endocrine tumor of the chromaffin cells in the adrenal medulla or the paraganglia. Currently, about 70% of PPGLs can be explained by germline or somatic mutations in several broadly expressed susceptibility genes including RET, VHL, and SDHB, while for the remaining, mainly sporadic cases, the pathogenesis is still unclear. Even for known susceptible genes, how mutations in these mostly ubiquitous genes result in tissue-specific pathogenesis remains unanswered, and why RET-mutated tumors almost always occur in the adrenal while SDHB-mutated tumors mostly occur extra-adrenal remains a mystery. By analyzing 22 sporadic PPGLs using SNP 6.0 genotyping arrays combined with expression profiling of 4 normal and 4 tumor tissues, we identified GIPC2, a gene located at 1p31.1 with preferential expression in adrenal and inducible by adrenal glucocorticoid, as a novel putative tumor suppressor gene for PPGLs. Copy number deletion and GIPC2 promoter hypermethylation but not GIPC2 mutation, accompanied with reduced GIPC2 expression, were observed in 39 of 55 PPGLs in our cohort. Examination of a published expression database consisting of 188 PPGLs found little GIPC2 expression in Cluster 1A (SDHx-associated) and Cluster 2A (NF1/RET-associated) tumors, but less pronounced reduction of GIPC2 expression in Cluster 1B (VHL-associated) and Cluster 2B/2C tumors. GIPC2 induced p27, suppressed MAPK/ERK and HIF-1ɑ pathways as well as cancer cell proliferation. Overexpressing GIPC2 in PC12 cells inhibited tumor growth in nude mice. We found GIPC2 interacted with the nucleoprotein NONO and both proteins regulated p27 transcription through the same GGCC box on p27 promoter. Significantly, low expression of both GIPC2 and p27 was associated with shorter disease-free survival time of PPGLs patients in the TCGA database. We found that PPGL-causing mutations in RET and in SDHB could lead to primary rat adrenal chromaffin cell proliferation, ERK activation, and p27 downregulation, all requiring downregulating GIPC2. Notably, the RET-mutant effect required the presence of dexamethasone while the SDHB-mutant effect required its absence, providing a plausible explanation for the tumor location preference. In contrast, the PPGL-predisposing VHL mutations had no effect on proliferation and GIPC2 expression but caused p53 downregulation and reduced apoptosis in chromaffin cells compared with wild-type VHL. Thus, our study raises the importance of cortical hormone in PPGL development, and GIPC2 as a novel tumor suppressor provides a unified molecular mechanism for the tumorigenesis of both sporadic and hereditary tumors of Clusters 1A and 2A concerning SDHB and RET, but not tumors of Cluster 1B concerning VHL and other clusters.

scholarly journals MEN4 and CDKN1B mutations: the latest of the MEN syndromes

2017 ◽  
Vol 24 (10) ◽  
pp. T195-T208 ◽  
Author(s):  
Rami Alrezk ◽  
Fady Hannah-Shmouni ◽  
Constantine A Stratakis
Keyword(s):  
Tumor Suppressor ◽  
Neuroendocrine Tumors ◽  
Pituitary Adenomas ◽  
Wide Spectrum ◽  
Susceptibility Gene ◽  
Germline Mutations ◽  
Suppressor Gene ◽  
Loss Of Function ◽  
Putative Tumor Suppressor

Multiple endocrine neoplasia (MEN) refers to a group of autosomal dominant disorders with generally high penetrance that lead to the development of a wide spectrum of endocrine and non-endocrine manifestations. The most frequent among these conditions is MEN type 1 (MEN1), which is caused by germline heterozygous loss-of-function mutations in the tumor suppressor geneMEN1. MEN1 is characterized by primary hyperparathyroidism (PHPT) and functional or nonfunctional pancreatic neuroendocrine tumors and pituitary adenomas. Approximately 10% of patients with familial or sporadic MEN1-like phenotype do not haveMEN1mutations or deletions. A novel MEN syndrome was discovered, initially in rats (MENX), and later in humans (MEN4), which is caused by germline mutations in the putative tumor suppressorCDKN1B. The most common phenotype of the 19 established cases of MEN4 that have been described to date is PHPT followed by pituitary adenomas. Recently, somatic or germline mutations inCDKN1Bwere also identified in patients with sporadic PHPT, small intestinal neuroendocrine tumors, lymphoma and breast cancer, demonstrating a novel role forCDKN1Bas a tumor susceptibility gene for other neoplasms. In this review, we report on the genetic characterization and clinical features of MEN4.

scholarly journals Overexpression of Uric Acid Transporter SLC2A9 Inhibits Proliferation of Hepatocellular Carcinoma Cells

2019 ◽  
Vol 27 (5) ◽  
pp. 533-540 ◽  
Author(s):  
Xiaoying Han ◽  
Jing Yang ◽  
Dong Li ◽  
Zewei Guo
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Uric Acid ◽  
Tumor Suppressor ◽  
Cell Apoptosis ◽  
Suppressor Gene ◽  
Potential Contribution ◽  
Acid Transporter ◽  
Underlying Mechanisms ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-associated mortality worldwide. Although the mechanisms of HCC progression are not well understood, recent studies demonstrated the potential contribution of uric acid transporter SLC2A9 to tumor suppression. However, the roles and underlying mechanisms are still unknown. We aimed to study the roles and mechanisms of SLC2A9 in HCC. The present study showed that SLC2A9 expression was decreased in human HCC tissues and cell lines. In addition, overexpression of SLC2A9 inhibited HCC cell proliferation. SCL2A9 induced HCC cell apoptosis by inhibiting the expression of caspase 3. Our study also revealed that upregulation of SLC2A9 reduced intracellular reactive oxygen species (ROS) accumulation. Furthermore, SLC2A9 increased the mRNA and protein expression of tumor suppressor p53 in HCC cells. Probenecid inhibits SLC2A9-mediated uric acid transport, which promotes cell proliferation, inhibits cell apoptosis, induces intracellular ROS, and decreases the expression of p53 in HCC cells. Therefore, the present study demonstrated that SLC2A9 may be a novel tumor suppressor gene and a potential therapeutic target in HCC.

Familial meningioma: analysis of expression of neurofibromatosis 2 protein Merlin

1998 ◽  
Vol 88 (3) ◽  
pp. 562-569 ◽  
Author(s):  
Marius Maxwell ◽  
Sarah D. Shih ◽  
Theofanis Galanopoulos ◽  
E. Tessa Hedley-Whyte ◽  
G. Rees Cosgrove
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Suppressor Gene ◽  
Protein Product ◽  
Neurofibromatosis 2 ◽  
Content Type ◽  
Spinal Meningiomas ◽  
Almost All ◽  
Second Tumor ◽  
Multistep Tumorigenesis

✓ Meningiomas are primarily benign brain tumors thought to arise through multistep tumorigenesis, involving both the activation of oncogenes and the loss of tumor suppressor genes. The recently isolated neurofibromatosis 2 (NF2) tumor suppressor gene has been found to be mutated in a large proportion of meningiomas. Almost all cases of familial meningioma occur in association with NF2. Familial meningioma in isolation from NF2 (sporadic) is exceedingly rare, with only 14 reports since 1959. The authors report the existence of a family lacking any stigmata of NF2, in which two members had spinal meningiomas. Tumor specimens were subjected to immunocytochemical analysis for the NF2 protein product Merlin, which has been implicated in the tumorigenesis of meningioma. Merlin immunoreactivity was present in both tumor specimens, implying that the NF2 tumor suppressor gene was not deleted in these tumors. This supports the hypothesis that a second tumor suppressor gene locus, other than NF2, acts in the formation of familial sporadic meningioma. The results are discussed in the context of putative oncogenic mechanisms of familial meningiomas.

scholarly journals ATP4B suppresses cell proliferation and migration via mitochondrial/p53/NF-κB pathway in gastric cancer

2020 ◽  
Author(s):  
Yuanming Pan ◽  
Yuqi He ◽  
Shuye Lin ◽  
Min Zhu ◽  
Yangjie Li ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Gastric Mucosa ◽  
Tumor Model ◽  
Suppressor Gene ◽  
Mitochondrial Pathway ◽  
Loss Of Function ◽  
Normal Tissues ◽  
And Migration ◽  
Induced Apoptosis

Abstract Background: Hydrogen/Potassium ATPase β (ATP4B) is a key protein in gastric mucosa barrier acting an essential role in gastric acid secretion. However, the exact role and precise mechanism of ATP4B in gastric cancer (GC) remain obscure. This study aimed to investigate the clinical significance of ATP4B in GC and its biological role in tumor progression.Methods: We evaluated ATP4B expression in GC cell lines and patient specimens via qPCR and Immunofluorescence. The correlations between ATP4B expression level and clinicopathologic parameters, as well as the relevance of ATP4B expression with overall survival were assessed. The functional roles of ATP4B in GC were verified by gain- and loss-of-function cell models and xenograft tumor model. The possible downstream effects of ATP4B were analyzed by iTRAQ‑based quantitative proteomics analysis.Results: A dramatic decrease of ATP4B expression in GC cells and tissues compared with the adjacent normal tissues was observed; Downexpression of ATP4B was associated with the malignant transformation in gastric mucosa lesions and correlated with poor prognosis, high grade of TNM stage, and vessel carcinoma embolus in GC patients. Restoration of ATP4B expression in GC cells significantly inhibited cell proliferation, cell viability, migration, invasion, tumorigenicity and induced apoptosis, whereas ATP4B silencing exerted the opposite effects. Mechanistically, we found a constitutive activation of p53 and inactivation of NF-κB signaling correlated with the mitochondrial pathway in ATP4B-overexpressing GC cells.Conclusion: Our data suggest that ATP4B perform the promising tumor suppressor gene by regulating p53/NF-κB/mitochondrial pathway in GC.

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