Merlin: the neurofibromatosis 2 tumor suppressor

Gusella, James F.; Ramesh, Vijaya; MacCollin, Mia; Jacoby, Lee B.

doi:10.1016/s0304-419x(99)00005-0

Cited by 68 publications

(74 citation statements)

References 44 publications

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“…2 and data not shown). The NF2 gene, which encodes the cytoskeleton-associated merlin protein, 32 was homozygously lost in 2 sam- Table 3. (B) Representative examples of HDs affecting the p16-INK4A/p14-ARF/p15-INK4B locus as visualized by PCR.…”

Section: Resultsmentioning

confidence: 99%

Homozygous Deletion Scanning in Hepatobiliary Tumor Cell Lines Reveals Alternative Pathways for Liver Carcinogenesis

et al. 2003

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Despite high rates of loss of heterozygosity affecting various chromosomes, the number of tumor suppressor genes (TSGs) found to be consistently involved in primary liver cancer is low. In the past decade, characterization of homozygous deletions (HDs) in tumors has become instrumental to identify new TSGs or to reveal the influence of a particular TSG on the development of a specific tumor type. We performed a detailed HD profiling at 238 critical loci on a collection of 57 hepatobiliary tumor cell lines (hepatocellular, cholangiocellular, and bile duct carcinomas, hepatoblastomas, and immortalized hepatocytes). We identified HDs at 9 independent loci, the analysis of which was extended to 17 additional hepatobiliary tumor cell lines. In total, 34 homozygous losses involving 9 distinct genes were detected in the 74 cell lines analyzed. Besides expected deletions at the p16-INK4A/p14-ARF, FHIT, AXIN1, and p53 genes, we detected HDs at the PTEN, NF2, STK11, BAX, and LRPDIT genes that were formerly not known to be implicated in human liver tumorigenesis. In conclusion, our data suggest that these genes may represent novel liver tumor suppressive targets. Additional tumorigenic pathways should be carefully considered in hepatocarcinogenesis. ( H epatocellular carcinoma (HCC), the main histologic form of primary liver cancer, is one of the most prevalent human tumors in the world. 1,2 Chronic infections of the liver by hepatitis B or hepatitis C viruses represent the dominant etiologies of HCC. 3 The historically recent spread of hepatitis C virus in human populations will result in a substantial increase in HCC incidence in developed countries and several epidemiologic surveys already have detected such a trend for the past 20 years in Japan, the United States, and Europe. 4,5 Until recently, chromosomal abnormalities occurring in HCC were defined poorly. We and others have performed allelotyping and comparative genomic hybridization studies to characterize the main chromosome targets in human liver tumorigenesis. 6-8 Only a handful of cancer genes are, however, consistently found mutated in this tumor type. p53 and AXIN1 genes are inactivated by somatic mutations in, respectively, 30% and 5% of cases, whereas p16-INK4A and SOCS1 are silenced through promoter hypermethylation in more than 50% of cases. 9-13 Finally, ␤-catenin, the only proto-oncogene previously found to be mutated in liver cancer, is activated in 20% of the samples. 14 The liver tumor-suppressive function of the product of the mannose-6-phosphate/insulinlike growth factor 2 receptor (IGF2/M6PR) gene is suspected but remains still controversial. 15,16 The past decade has seen the isolation of numerous tumor suppressor genes (TSGs) through the characterization of homozygous deletions (HDs) in primary tumors and cell lines. Although, HDs represent rare events, many of the TSG isolations, including WT1, p16-INK4A, BRCA2, FHIT, PTEN, SMAD4, and SNF5, were at least partly attributable to their detection. [17][18][19][20][21][22] In an attempt to

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Section: Resultsmentioning

confidence: 99%

Homozygous Deletion Scanning in Hepatobiliary Tumor Cell Lines Reveals Alternative Pathways for Liver Carcinogenesis

et al. 2003

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“…Merlin has been reported to interact with several proteins and has been implicated in a range of cellular and molecular functions (Gusella et al, 1999;McClatchey and Giovannini, 2005). One of the key questions regarding merlin function is whether it performs multiple independent functions, one of which is critical for tumor suppression, or whether merlin regulates a specific combination of pathways that collectively impart tumor suppression.…”

Section: Discussionmentioning

confidence: 99%

Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK

et al. 2006

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The neurofibromatosis type 2 NF2 gene product, merlin, is a tumor suppressor frequently inactivated in malignant mesothelioma (MM). To investigate a possible correlation between merlin inactivation and MM invasiveness, we restored merlin expression in NF2-deficient MM cells. Re-expression of merlin markedly inhibited cell motility, spreading and invasiveness, properties connected with the malignant phenotype of MM cells. To test directly whether merlin inactivation promotes invasion in a nonmalignant system, we used small interfering RNA to silence Nf2 in mouse embryonic fibroblasts (MEFs) and found that downregulation of merlin resulted in enhanced cell spreading and invasion. To delineate signaling events connected with this phenotype, we investigated the effect of merlin expression on focal adhesion kinase (FAK), a key component of cellular pathways affecting migration and invasion. Expression of merlin attenuated FAK phosphorylation at the critical phosphorylation site Tyr397 and disrupted the interaction of FAK with its binding partners Src and p85, the regulatory subunit of phosphatidylinositol-3-kinase. In addition, NF2-null MM cells stably overexpressing FAK showed increased invasiveness, which decreased significantly when merlin expression was restored. Collectively, these findings suggest that merlin inactivation is a critical step in MM pathogenesis and is related, at least in part, with upregulation of FAK activity.

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“…Specifically, these include mutations of the NF2 gene (chromosome 22q12.2), which codes for the protein merlin, a tumor suppressor gene. Merlin is lost in different meningioma types, while Yes-associated protein (YAP) is increased, resulting in meningioma proliferation [89]. Loss of 1p is the second most common chromosomal abnormality, correlated to ELAVL4 gene which reveals a distinct gender difference [90], and to ALPL (1p36.1-p34) which is down regulated, associated with high grade tumors and recurrence [88].…”

Section: Ancillary Techniquesmentioning

confidence: 99%