POSSIBLE INTERACTION OF CELL MEMBRANE- BOUND N-ras PATHWAYS WITH NF2-RELATED CYTOSKELETON FACTORS IN ONCOGENESIS OF MENINGIOMAS
Yapijakis C1, Mamali I1, Papapetrou KP2, Stranjalis GS2, Protopapa DP3, Vassilopoulos D1, Sakas DE2
*Corresponding Author: Christos Yapijakis, D.M.D., M.S., Ph.D., Department of Neurology, University of Athens Medical School, Eginition Hospital, Vas Sofias 74, Athens 11528, Greece; Tel: +30-10-7289-125; Fax: +30-10-8811-243; E-mail: cyapijakis_ua_gr@yahoo.com
page: 17

DISCUSSION

Several genes have been shown to carry mutations in meningiomas, with the NF2 gene being most frequently affected. Mutations have been found in the sis, PTEN and p53 genes [8], but very few reports have implicated the N-ras, H-ras and K-ras genes in the development of menin­giomas [8,9].

In this study, we assessed the role of NF2 and N-ras, simultaneously, in meningioma samples of different grades. Our preliminary results indicate a significant role for N-ras in oncogenesis of meningiomas, since protein p21N-ras was undetected in one and overexpressed in nine samples (71.4%). It is of interest that the over-expression of N-ras was observed in grade II or grade III samples (89% of them), suggesting a role in the advanced stage of oncogenesis.

The possibility of interaction between the N-ras and merlin pathways is raised by the observation that absence of N-ras was detected in a grade I meningioma that carried an NF2 mutation. Thus, absence of N-ras may decrease the effect of NF2 loss towards advancement of malignancy.

The N-ras pathway of cell growth signaling and control has not yet been linked with cytoskeleton factors in a definite way. In mammalian cells ras proteins activate a cascade of serine/threonine protein kinases that includes RAF1, mitogenactivated protein kinase kinase (MAPKK) and extracellular signal-regulated kinases (ERKs or MAP kinases) [13]. The NF2 protein is phosphorylated on serine/ threonine residues, and is probably involved in signaling growth inhibitory pathways [7]. This suggests that a serine/ threonine protein kinase pathway may be the interaction point of the N-ras and merlin pathways.

In this study we found evidence that an abnormality in the two pathways may have an additive effect in tumorigenic steps towards malignancy of meningiomas. Mutation analysis in other hot spot codons of the NF2 gene is in progress for these meningioma samples. Obviously, a larger series of meningiomas needs to be studied in order to demonstrate any possible interaction of the N-ras and the NF2 pathways of cell growth control.

 

 

 

 

 

 

 

 

 

 

Figure 2. Immunohistochemical detection of normal p21 N-ras protein in meningioma sections, using a primary c-N-ras antibody. a) Sural nerve biopsy (control for immu­nostaining); b) + result in sample 4659 (about equal inten­sity with control); c) +++ result in sample 513 (increased intensity compared to control); d) result in sample 5065 (decreased intensity compared to control).

 




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