Analysis of the <i>NF2</i> tumor‐suppressor gene and of chromosome 22 deletions in gliomas

Hoano-Xuan, Khě; Meree, Philippe; Vega, F; Hugot, Jean‐Pierre; Cornu, Philippe; Delattre, Jean‐Yves; Poisson, M; Thomas, Gilles; Delattre, Olivier

doi:10.1002/ijc.2910600409

Cited by 44 publications

(27 citation statements)

References 23 publications

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“…The LIMK1 gene was recently suggested to be one of the causal genes of Williams' syndrome [17]. The locus of the LIMK2 gene is close to that of the tumor suppressor gene NF2 (neurofibromatosis 2) [24], Since loss on 22q near to but outside the NF2 locus was detected in some cases of menigiomas, gliomas, ovarian carcinoma and colorectal cancers [25][26][27], inactivation of the LIMK2 gene may be linked to the tumorigenesis of these cancers.…”

Section: Discussionmentioning

confidence: 99%

Suppression of fibroblast cell growth by overexpression of LIM‐kinase 1

et al. 1996

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LIM-kinase 1 (LIMK1) is a serine/threonine kinase containing two LIM motifs at the N-terminus. The functional role of LIMK1 has remained unknown. In this study, we examined the role of LIMK1 in cell growth of fibroblasts. Induced expression of LIMK1 in NIH3T3 cells led to growth retardation• Transfection of LIMK1 sense cDNA into NIH3T3 and H-ras-transformed FYJ10 fibroblasts significantly suppressed colony formation of these cells. In contrast, transfection with LIMK1 antisense cDNA strongly stimulated colony tormation of the NIH3T3 cells• These findings suggest that I~IMK1 functions as a negative regulator of fibroblast cell ~:rowth, and may play a role in tumor suppression.i£ey words: Growth suppression; Protein kinase; LIM motif: J)HR/PDZ domain; LIMK • Introductionthreonine kinase activity and is mainly localized in the cytoplasm [3]. The LIMK1 gene was assigned on human chromosome 7q11.23 [3], and a recent report suggests that hemizygosity of the LIMK1 gene leads to impaired visuospatial cognition in patients of Williams' syndrome [17]. The unique structural features of LIMK family kinases suggest their specific roles in previously uncharacterized signaling pathways, but the cellular functions of these kinases remain to be determined. We have now examined the effects of overexpression of LIMK1 on cell proliferation of NIH3T3 and Ras-transformed FYJI0 fibroblasts. Using an induced expression system and colony formation assay, we found that ectopic expression of LIMKI significantly suppressed cell growth of NIH3T3 and Ras-transformed fibroblasts, Transfection of the antisense LIMKI cDNA stimulated colony formation of NIH3T3 cells. The evidence that LIMKI has an anti-proliferative activity on fibroblasts represents the first demonstration of cellular functions of LIMK family kinases.We recently identified a novel class of closely related pro~ein kinases, termed LIM-kinases (LIMKs), composed of ~IMK1 and LIMK2 [14]. These kinases contain characterstic structural features of the two N-terminal LIM motifs, the nternal DHR (Dig homology region) (also called PDZ or ,]LGF) domain, and the unusual C-terminal protein kinase , lomain. The LIM motif, a structural motif composed of two tdjacent zinc fingers separated by a 2-amino-acid linker, is ound in diverse proteins, including homeodomain-containing ranscription factors, cytoskeletal proteins and other signaling nolecules [5,6]. The DHR domain is a 90 100-amino-acid notif, previously found in various cell-junction proteins and ~'nzymes [7,8]. Since both of these domains are thought to 'unction as the binding surfaces of protein-protein interacions [9 13], they are likely to be involved in the regulation )f kinase activity and subcellular localization of LIMK family ~roteins. The C-terminal kinase domains of LIMKs contain a :onsensus sequence of protein kinases, but are unique in that hey have an unusual sequence motif (DLNSHN) in the kilase catalytic loop in subdomain VIB and a highly basic kiaase insert between subdomains VII and VIII [14].LIMK1 mRNA is hi...

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Section: Discussionmentioning

confidence: 99%

Suppression of fibroblast cell growth by overexpression of LIM‐kinase 1

et al. 1996

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“…Loss of heterozygosity on chromosome arm 22q occurs in approximately 20-30% of diffuse astrocytomas, regardless of malignancy grade, suggesting the presence of a tumor suppressor gene involved in early astrocytic glioma development (89)(90)(91)(92)(93). A recent report by Ino et al (89) has defined two minimal deletion regions on 22q.…”

Section: Chromosome 22mentioning

confidence: 99%

Genetic alterations in adult diffuse glioma: occurrence, significance, and prognostic implications

Smith

Jenkins²

2000

Front Biosci

146

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Our understanding of diffuse glioma development and progression has expanded remarkably over the past decade. As the genetic alterations responsible for these tumors are identified, molecular models of glioma pathogenesis are emerging and hold great promise to explain the biologic mechanisms of these neoplasms. Although these models continue to evolve and remain highly simplified, some of the genetic alterations that they encompass appear to be prognostically useful. Among the astrocytic gliomas, age and tumor grade are the most powerful indicators of patient survival, however, a wide range of variability remains, particularly among the lowgrade and anaplastic astrocytomas. Recent reports indicate that alterations of the PTEN tumor suppressor gene are independent predictors of overall survival for anaplastic astrocytoma patients, helping to distinguish the cases with behavior resembling their more malignant counterparts, the glioblastomas.Among the oligodendroglial tumors, alterations of the 1p and 19q chromosome arms have emerged as potentially powerful predictors of overall patient survival and in vivo chemotherapeutic response, while alterations of the p16/CDKN2A tumor suppressor gene suggest shorter overall survival. As our molecular models continue to improve, through functional analyses and the identification of additional genetic contributors, we will expand our capacity to more effectively prognose these patients and to design rational therapeutic strategies. INTRODUCTIONDiffuse gliomas exhibit an inherent tendency to progress to more malignant phenotypes and a broad range of clinical behavior. Classification of diffuse gliomas by histologic subtype (figure 1) and malignancy grade (figure 2),

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“…Although malignant gliomas often have LOH on chromosome 22, this finding does not translate into mutations in the NF2 gene. [14] Instead, mutations in the NF2 gene associated with spinal ependymomas are found with a higher frequency in these patients. The nature of the gene mutations in Turcot syndrome and TS have not been well defined enough to draw any inferences of their role in glioma oncogenesis.…”

Section: Relationship Between Hereditary Neurological Tumor Syndromesmentioning

confidence: 96%

“…They did not find any mutations in the astrocytomas but found a mutation in a spinal ependymoma. Hoang-Xuan, et al, [14] found loss of heterozygosity (LOH) in chromosome 22 in 17 of 70 gliomas (World Health Organization [WHO] Grades II-IV astrocytomas, oligodendrogliomas, and oligoastrocytomas). They screened the samples with LOH in chromosome 22 for the mutations in the NF2 gene and did not find any mutations, leading them to conclude that NF2 gene mutations are not important for astrocytoma and oligodendroglioma tumorigenesis.…”

Section: Neurofibromatosis Typementioning

confidence: 99%

Hereditary neurological tumor syndromes: clues to glioma oncogenesis?

Chen

Yarosh²,

Garcia³

et al. 1998

FOC

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The author reviewed five hereditary neurological tumor syndromes associated with gliomas: Li-Fraumeni cancer syndrome, neurofibromatosis type 1 (NF1) and type 2 (NF2), tuberous sclerosis (TS), and Turcot syndrome. In each case, clinical manifestation, genetic localization, and protein function were identified. Correlation with glioma oncogenesis demonstrated the following associations: 1) p53 mutation (Li-Fraumeni) with astrocytoma progression; 2) NF1 mutation (NF1) with pilocytic astrocytomas; and 3) NF2 mutation (NF2) with ependymoma formation. The role of the TS gene and the adenomatous polypopsis coli gene (Turcot syndrome) in glioma oncogenesis is not clear. Because tumorigenesis is a multistep process, it would be premature to equate a specific germline mutation with the multiple somatic mutations required for glioma formation. However, identification of specific germline genetic mutations provides a model for the multiple tumor suppressor genes involved in glioma pathogenesis.

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Analysis of the NF2 tumor‐suppressor gene and of chromosome 22 deletions in gliomas

Cited by 44 publications

References 23 publications

Suppression of fibroblast cell growth by overexpression of LIM‐kinase 1

Suppression of fibroblast cell growth by overexpression of LIM‐kinase 1

Genetic alterations in adult diffuse glioma: occurrence, significance, and prognostic implications

Hereditary neurological tumor syndromes: clues to glioma oncogenesis?

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