Disease relevance of EPB41L3

• In this report, we demonstrate DAL-1 loss in 60% of sporadic meningiomas using LOH, RT-PCR, western blot and immunohistochemistry analyses [1].
• 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 [1].
• DAL-1 (differentially expressed in adenocarcinoma of the lung)/4.1B is a tumor suppressor gene on human chromosome 18p11.3 whose expression is lost in >50% of primary non-small-cell lung carcinomas [2].
• Recently, we determined that expression of a second Protein 4.1 tumor suppressor, DAL-1, was lost in 60% of sporadic meningiomas, but not schwannomas [3].
• In contrast, a pilot study suggested that 4.1B deletions might be more common in intracranial ependymomas [4].

High impact information on EPB41L3

• 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 [1].
• Loss of DAL-1, a protein 4.1-related tumor suppressor, is an important early event in the pathogenesis of meningiomas [1].
• Previous studies from our laboratory have shown that protein 4.1B growth suppression in meningioma is associated with the activation of the c-Jun-NH(2)-kinase (JNK) pathway and requires localization of a small unique region (U2 domain) of protein 4.1B to the plasma membrane [5].
• Protein 4.1B/differentially expressed in adenocarcinoma of the lung-1 functions as a growth suppressor in meningioma cells by activating Rac1-dependent c-Jun-NH(2)-kinase signaling [5].
• Here, we report that TSLC1 directly associates with DAL-1, a gene product of another lung tumor suppressor belonging to the protein 4.1 family [6].

Chemical compound and disease context of EPB41L3

• Re-expression of TSLC1 and DAL-1 was seen after treatment of lung cancer cell lines with 5-aza-2'-deoxycytidine [7].

Biological context of EPB41L3

• Allele-specific loss of heterozygosity at the DAL-1/4.1B (EPB41L3) tumor-suppressor gene locus in the absence of mutation [8].
• In tumors of NSCLC patients with stage II-III disease, DAL-1 methylation was seen at a statistically significant higher frequency compared to tumors of patients with stage I disease [7].
• In this report, we demonstrate that DAL-1 suppresses cell proliferation in meningioma, but not schwannoma cells [3].
• The protein 4.1 tumor suppressor, DAL-1, impairs cell motility, but regulates proliferation in a cell-type-specific fashion [3].
• The majority of cases harbored one or more detectable genetic alterations, but we found that 4.1B gene deletions and 4.1R loss of expression were statistically more common in the pediatric vs adult, intracranial vs spinal, and grade III vs grade I/II subsets (P-values of 0.038 to <0.001) [4].

Anatomical context of EPB41L3

• DAL-1/4.1B is normally expressed at high levels in the brain, with lower levels in the kidney, intestine, and testis [9].
• We propose that 4.1B anchors these axonal proteins to the actin-based cytoskeleton in these two regions [10].
• Immunocytochemical staining with a polyclonal anti-DAL-1 antibody localized the protein to the plasma membrane, particularly at cell-cell contact points, a pattern reminiscent of other members of the protein 4.1 superfamily including ezrin and NF2 [11].
• In addition, expression of DAL-1 increased attachment of these cells to a variety of extracellular matrices [12].
• Human DAL-1 was also expressed in matured epithelial cells in human colons, with a definite expression gradient along the crypt axis [13].

Associations of EPB41L3 with chemical compounds

• Moreover, similar to wild-type DAL-1, the stable expression of the DAL-1 F359Y mutant significantly reduced cell proliferation in independently isolated IOMM-Lee clones, as assessed by thymidine incorporation [14].
• Expression and allelic and methylation status of DAL-1 was examined by reverse transcription-PCR, microsatellite analysis, and bisulfite sequencing or bisulfite single-strand conformational polymorphism, respectively [15].
• Similar to the Protein 4.1B and merlin tumor suppressors, Protein 4.1R membrane localization increased significantly under conditions of growth arrest in vitro [16].
• Moreover, the immunolocalization of protein 4.1B was almost the same as that of NBC-1, indicating a possible function as a regulator of ion balance, such as Na(+) and HCO(3)(-) reabsorption [17].

Other interactions of EPB41L3

• Our results suggest that methylation of TSLC1 and/or DAL-1, leading to loss of their expression, is an important event in the pathogenesis of NSCLC [7].
• However, little is known about the other two genes in this cascade, DAL-1 and MPP3 [7].
• In this study, we assessed the impact of DAL-1/4.1B binding on the activity of another family member, PRMT5, both in vitro and in cells [18].
• This was due to a decrease in the ability of 4.1G and 4.1B SAB domain to interact with actin but not with spectrin [19].
• Comparative transcript abundance was analysed in heart and brain. betaIISigma2-spectrin was the most abundant transcript in heart with levels 5 fold greater than 4.1G or 4.1N and at least 9 fold greater than 4.1B [20].

Analytical, diagnostic and therapeutic context of EPB41L3

• Complementary in vitro GST affinity chromatography and in vivo interaction experiments demonstrated that the F359Y mutation abrogated binding to 14-3-3, but did not impair DAL-1 binding to other known Protein 4.1B interacting proteins [14].
• Furthermore, in adenocarcinomas, disease-free survival and overall survival were significantly shorter in patients with tumors harboring the methylated DAL-1 (P = 0.0011 and P = 0.045, respectively) [15].
• Fluorescence in situ hybridization (FISH) was performed using 1p/1q, 19p/19q, CEP18/DAL1, and bcr/NF2 probe pairs [21].
• By immunoelectron microscopy, protein 4.1B immunolabeling of the proximal epithelial cells was restricted to the basolateral membranes, including basal infoldings, whereas tight junctions were not immunolabeled [17].
• In this study, we extended the idea that protein 4.1B may be related to ion balance in the region by immunohistochemical studies by light and electron microscopy with our antibody against protein 4.1B [17].

References