The NF2 gene and merlin protein in human osteosarcomas

Stemmer‐Rachamimov, Anat; Nielsen, G. Petur; Rosenberg, Andrew E.; Louis, David N.; Jones, Deborah; Ramesh, Vijaya; Gusella, James F.; Jacoby, Lee B.

doi:10.1007/s100480050054

Cited by 19 publications

(13 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, the low incidence and late onset of schwannomas, in contrast to the high incidence of SC hyperplasia in P0-Cre;Nf2 flox2/flox2 mice strongly suggest that an additional mutation is required for the progression of SC hyperplasia to tumor formation (Giovannini et al 1999(Giovannini et al , 2000Stemmer-Rachamimov et al 2004). Documentation of biallelic NF2 inactivation in preneoplastic lesions (hyperplastic SCs and tumorlets) of NF2 patients also supports this hypothesis (Stemmer-Rachamimov et al 1998).…”

Section: Future Directions/perspectivesmentioning

confidence: 65%

Membrane organization and tumorigenesis—the NF2 tumor suppressor, Merlin

McClatchey¹,

Giovannini²

2005

Genes Dev.

250

205

View full text Add to dashboard Cite

The NF2 tumor-suppressor gene was cloned more than a decade ago, but the function of its encoded protein, Merlin, remains elusive. Merlin, like the closely related ERM proteins, appears to provide regulated linkage between membrane-associated proteins and the actin cytoskeleton and is therefore poised to function in receiving and interpreting signals from the extracellular milieu. Recent studies suggest that Merlin may coordinate the processes of growth-factor receptor signaling and cell adhesion. Varying use of this organizing activity by different types of cells could provide an explanation for the unique spectrum of tumors associated with NF2 deficiency in mammals.The identification of the genetic defect responsible for the familial cancer syndrome Neurofibromatosis type 2 (NF2) nearly 15 years ago yielded the unexpected prospect that the encoded tumor suppressor was a cytoskeleton-associated protein (Rouleau et al. 1993;Trofatter et al. 1993). This was in marked contrast to the known and now "classic" tumor suppressors p53, Rb, and NF1 that function either to directly control the cell cycle machinery in the nucleus, or in the case of NF1, to directly negatively regulate mitogenic Ras signaling (Sherr 2004). Several factors have rendered progress in defining the molecular basis of NF2-associated tumorigenesis slow, including the rare incidence of NF2 in humans, the paucity of NF2 −/− cell lines and technical challenges in studying the NF2-encoded protein, Merlin, which is a novel type of tumor suppressor. However, recent advances, highlighted by the study of NF2 function in several different model organisms have begun to yield a model of Merlin function that offers important lessons about the origins and progression of cancer and provides novel insight into some basic biological principles. In this review we have highlighted recent advances in understanding the pathology and molecular biology of NF2 with particular emphasis on the broader impact that the study of NF2 may have on the fields of tumor, cellular, and molecular biology.The incidence of NF2 in humans is rare (fewer than one in 25,000 individuals) and the symptoms and phenotypes associated with NF2 are unusual and restricted (Evans et al. 2005). The hallmark of the disease is the development of Schwann cell tumors (schwannomas) on or around the vestibular branch of both eighth cranial nerves. Most NF2 patients go on to develop multiple schwannomas that are associated with other cranial nerves and spinal nerve roots, cranial and spinal meningiomas and, less frequently, intraspinal ependymomas. In contrast to other major human malignancies, these are benign, slow-growing tumors that respond poorly to chemotherapeutic intervention and cause significant morbidity. Indeed, the current standard of treatment remains local tumor control by repeated surgeries and radiation, which are often accompanied by damage of nerves and CNS structures (Evans et al. 1992).Biallelic inactivation of the NF2 gene can also be identified in most sporadically occurring schwann...

show abstract

Section: Future Directions/perspectivesmentioning

confidence: 65%

Membrane organization and tumorigenesis—the NF2 tumor suppressor, Merlin

McClatchey¹,

Giovannini²

2005

Genes Dev.

250

205

View full text Add to dashboard Cite

show abstract

“…However, follow-up studies using human osteosarcoma tumors found no alteration in NF2 (ref. 72). Notably, the osteosarcomas seen in Nf2 -null mice were not extensively tested for spontaneous Trp53 loss.…”

Section: Discussionmentioning

confidence: 99%

A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis

et al. 2015

View full text Add to dashboard Cite

Osteosarcomas are sarcomas of the bone, derived from osteoblasts or their precursors, with a high propensity to metastasize. Osteosarcoma is associated with massive genomic instability, making it problematic to identify driver genes using human tumors or prototypical mouse models, many of which involve loss of Trp53 function. To identify the genes driving osteosarcoma development and metastasis, we performed a Sleeping Beauty (SB) transposon-based forward genetic screen in mice with and without somatic loss of Trp53. Common insertion site (CIS) analysis of 119 primary tumors and 134 metastatic nodules identified 232 sites associated with osteosarcoma development and 43 sites associated with metastasis, respectively. Analysis of CIS-associated genes identified numerous known and new osteosarcoma-associated genes enriched in the ErbB, PI3K-AKT-mTOR and MAPK signaling pathways. Lastly, we identified several oncogenes involved in axon guidance, including Sema4d and Sema6d, which we functionally validated as oncogenes in human osteosarcoma.

show abstract

“…Transgenic mice overexpressing c-Fos develop OS and chondrosarcoma, and Fos overexpression has also frequently been observed in human OS (Ruther et al 1989;Wu et al 1990;Wang et al 1995). Heterozygous mutation of Nf2 results in the development of OS in mouse (>60% penetrance), yet human neurofibromatosis 2 patients do not normally develop OS nor are mutations in Nf2 found in human OS samples (McClatchey et al 1998;Stemmer-Rachamimov et al 1998). While these models provide important information regarding the genetics of OS, the long latency combined with low penetrance makes utilization of these models impractical.…”

mentioning

confidence: 99%

Conditional mouse osteosarcoma, dependent on p53 loss and potentiated by loss of Rb, mimics the human disease

Walkley

Qudsi²,

Sankaran³

et al. 2008

Genes Dev.

330

370

View full text Add to dashboard Cite

Osteosarcoma is the most common primary malignant tumor of bone. Analysis of familial cancer syndromes and sporadic cases has strongly implicated both p53 and pRb in its pathogenesis; however, the relative contribution of these mutations to the initiation of osteosarcoma is unclear. We describe here the generation and characterization of a genetically engineered mouse model in which all animals develop short latency malignant osteosarcoma. The genetically engineered mouse model is based on osteoblast-restricted deletion of p53 and pRb. Osteosarcoma development is dependent on loss of p53 and potentiated by loss of pRb, revealing a dominance of p53 mutation in the development of osteosarcoma. The model reproduces many of the defining features of human osteosarcoma including cytogenetic complexity and comparable gene expression signatures, histology, and metastatic behavior. Using a novel in silico methodology termed cytogenetic region enrichment analysis, we demonstrate high conservation of gene expression changes between murine osteosarcoma and known cytogentically rearranged loci from human osteosarcoma. Due to the strong similarity between murine osteosarcoma and human osteosarcoma in this model, this should provide a valuable platform for addressing the molecular genetics of osteosarcoma and for developing novel therapeutic strategies.[Keywords: Cancer; mouse model; osteocarcinoma] Supplemental material is available at http://www.genesdev.org.

show abstract

The NF2 gene and merlin protein in human osteosarcomas

Cited by 19 publications

References 0 publications

Membrane organization and tumorigenesis—the NF2 tumor suppressor, Merlin

Membrane organization and tumorigenesis—the NF2 tumor suppressor, Merlin

A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis

Conditional mouse osteosarcoma, dependent on p53 loss and potentiated by loss of Rb, mimics the human disease

Contact Info

Product

Resources

About