Compensative shuttling of merlin to phosphorylation on serine 518 in vestibular schwannoma.
BACKGROUND
Vestibular schwannoma (VS) is a benign tumor with malignant biological consequence because of its special location, and its occurrence is highly related to merlin. Cell culture studies have demonstrated that merlin acts as a molecular linker between the cytoskeleton and specific membrane proteins and is linked to cell cycle control. Therefore, we sought to detect the expression of endogenous merlin and its subcellular distribution using cyclin D1 as a cell cycle marker in VS.


METHODS
To confirm endogenous merlin protein expression in abiogenous VS cells, in situ hybridization, immunohistochemistry, and Western blot was performed in tumor tissues surgically resected from patients. Merlin's subcellular distribution linked cell cycle in VS was analyzed and compared with cyclin D1 expression evaluated with confocal microscopy.


RESULTS
We found that merlin appeared in 98% of the VS tissue samples, with a mean cellular positivity of 46.66 +/- 5.75%. Merlin is inversely correlated with cyclin D1 in regard to subcellular localization. Merlin locates in the cytoplasm during G0/G1 phase, moves to the nucleus at S phase, and accumulates in the cytoplasm at S phase after phosphorylation on serine 518 (S518).


CONCLUSIONS
In line with the pathologic characteristic of VS as a benign tumor, merlin compensates for the malignant effect of S518 phosphorylation by limiting the loss of contact inhibition of growth and controlling proliferation. S518 phosphorylation can trigger re-entry into the cell cycle, failing to control transcription because of mislocalization and an inability to interact with the cytoskeleton.
Lü
Jingrong
J
Department of Otolaryngology-Head and Neck Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Zou
Jing
J
Wu
Hao
H
Cai
Lihui
L
D021581:Active Transport, Cell Nucleus; D001693:Biological Transport, Active; D002453:Cell Cycle / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism / Q000648:ultrastructure; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism / Q000648:ultrastructure; D005455:Fluorescent Antibody Technique; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D018613:Microscopy, Confocal; D025581:Neurofibromin 2 / Q000235:genetics / Q000378:metabolism*; D009464:Neuroma, Acoustic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D016192:Resting Phase, Cell Cycle; D016196:S Phase; D012694:Serine / Q000378:metabolism*
D025581:Neurofibromin 2; D019938:Cyclin D1; D012694:Serine