Loss of DAL-1, a protein 4.1-related tumor suppressor, is an important early event in the pathogenesis of meningiomas.
Meningiomas are common nervous system tumors, whose molecular pathogenesis is poorly understood. To date, the most frequent genetic alteration detected in these tumors is loss of heterozygosity (LOH) on chromosome 22q. This finding led to the identification of the neurofibromatosis 2 (NF2) tumor suppressor gene on 22q12, which is inactivated in 40% of sporadic meningiomas. The NF2 gene product, merlin (or schwannomin), is a member of the protein 4.1 family of membrane-associated proteins, which also includes ezrin, radixin and moesin. Recently, we identified another protein 4.1 gene, DAL-1 (differentially expressed in adenocarcinoma of the lung) located on chromosome 18p11.3, which is lost in approximately 60% of non-small cell lung carcinomas, and exhibits growth-suppressing properties in lung cancer cell lines. Given the homology between DAL-1 and NF2 and the identification of significant LOH in the region of DAL-1 in lung, breast and brain tumors, we investigated the possibility that loss of expression of DAL-1 was important for meningioma development. In this report, we demonstrate DAL-1 loss in 60% of sporadic meningiomas using LOH, RT-PCR, western blot and immunohistochemistry analyses. Analogous to merlin, we show that DAL-1 loss is an early event in meningioma tumorigenesis, suggesting that these two protein 4.1 family members are critical growth regulators in the pathogenesis of meningiomas. Furthermore, our work supports the emerging notion that membrane-associated alterations are important in the early stages of neoplastic transformation and the study of such alterations may elucidate the mechanism of tumorigenesis shared by other tumor types.
Gutmann
D H
DH
Departments of Neurology and Neuropathology, Washington University School of Medicine, St Louis, MO 63110, USA. gutmannd@neuro.wustl.edu
Donahoe
J
J
Perry
A
A
Lemke
N
N
Gorse
K
K
Kittiniyom
K
K
Rempel
S A
SA
Gutierrez
J A
JA
Newsham
I F
IF
D000818:Animals; D015153:Blotting, Western; D002887:Chromosomes, Human, Pair 18; D003598:Cytoskeletal Proteins; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D008577:Meningeal Neoplasms / Q000235:genetics*; D008579:Meningioma / Q000235:genetics*; D008840:Microfilament Proteins; D009442:Neurilemmoma / Q000235:genetics / Q000378:metabolism; D025581:Neurofibromin 2; D009479:Neuropeptides; D018807:Polymorphism, Single-Stranded Conformational; D017434:Protein Structure, Tertiary; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012583:Schwann Cells / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D003598:Cytoskeletal Proteins; C116887:EPB41L3 protein, human; D008565:Membrane Proteins; D008840:Microfilament Proteins; D025581:Neurofibromin 2; D009479:Neuropeptides; D025521:Tumor Suppressor Proteins; C028841:erythrocyte membrane band 4.1 protein; C120557:erythrocyte membrane protein band 4.1-like 1