Disease relevance of DLEC1

• One gene of particular interest was DLEC1, located at a commonly deleted area on chromosome 3p22-p21.3, which was frequently methylated in primary lung cancers and melanomas [1].
• DLEC1, Deleted in Lung and Esophageal Cancer 1, located at 3p22.2, was recently identified as a candidate tumor suppressor gene in lung, esophageal, and renal cancers [2].
• The potential involvement of DLEC1 in epithelial ovarian cancer remains unknown [3].
• Deleted in Lung and Esophageal Cancer 1 (DLEC1) on 3p22.3 is a candidate tumor suppressor in lung, esophageal, and renal cancers [3].
• We report that cten binds to another tumor suppressor, deleted in liver cancer 1 (DLC-1), and the SH2 domain of cten is responsible for the interaction [4].

High impact information on DLEC1

• These results provide a novel mechanism whereby the SH2 domain of cten-mediated focal adhesion localization of DLC-1 plays an essential role in its tumor suppression activity [4].
• The phosphotyrosine-independent interaction of DLC-1 and the SH2 domain of cten regulates focal adhesion localization and growth suppression activity of DLC-1 [4].
• Unexpectedly, the interaction between DLC-1 and the cten SH2 domain is independent of tyrosine phosphorylation of DLC-1 [4].
• Overlapping double (dlec1) or triple (dlec2) polyadenylation addition signals are found and there is an unusually high degree of homology (84%) between their 3'-untranslated regions.(ABSTRACT TRUNCATED AT 250 WORDS)[5]
• On the basis of the deduced amino acid sequences and compositions and the mol. wts. of their encoded glycoproteins, the genes, dlec1 and dlec2, are predicted to encode erythro- and leucoagglutinating phytohemagglutinins (PHA-E and PHA-L), respectively [5].

Biological context of DLEC1

• Molecular cloning of a candidate tumor suppressor gene, DLC1, from chromosome 3p21.3 [6].
• Down-regulation of DLEC1 and promoter hypermethylation were observed in all NPC cell lines and xenografts but not in normal nasopharyngeal epithelial cells [2].
• DLEC1 promoter methylation was examined in 13 high-grade ovarian tumor tissues with DLEC1 downregulation, in which 54% of the tumors showed DLEC1 methylation [3].
• This promoter hypermethylation inversely correlated with DLC-1 gene expression in primary NHL samples [7].
• Although all of the F56 mutations disrupt the GSH binding site, the effects of the mutations on the structure of the subunit interface and dimer stability are quite distinct [8].

Anatomical context of DLEC1

• These data suggest that aberrant transcription of this gene, designated DLC1 (deleted in lung cancer 1), may be involved in carcinogenesis of the lung, esophagus, and kidney [6].
• Promoter hypermethylation of DLEC1 was detected in ovarian cancer cell lines with reduced DLEC1 transcripts, whereas methylation was not detected in normal ovarian epithelium and DLEC1-expressing ovarian cancer cell lines [3].
• When these DLC-1 mutants were fused to a focal adhesion targeting sequence, their tumor suppression activities were significantly restored [4].
• In a FACS analysis, MAbs F56 and F119 detected IRTA2 expression in six of seven B cell non-Hodgkin's lymphoma and one of six Burkitt's lymphoma cell lines [9].

Associations of DLEC1 with chemical compounds

• Disruption of the complementary interactions in this motif by mutation of F56 to serine, arginine, or glutamate is known to have deleterious effects on catalytic efficiency but remarkably different effects on the stability of the dimer [Hornby et al. (2002) Biochemistry 41, 14238-14247] [8].
• Molecular modeling using coordinates for the recently determined N-terminal domain of human SBP revealed a significant shift of the F56 phenyl ring away from ring A of E(2) in mutant models containing the R140K and I141L replacements [10].
• Bisulfite sequencing further verified a densely methylated pattern of 35 CpG sites studied in M1 that were not found in normal brain, indicating that inactivation of DLC-1 by hypermethylation is involved in SPNET [11].
• We conclude that R140 and I141 are required for sustaining the right proximity of the phenyl ring of F56 to ring A of 17beta-estradiol, thus optimizing the E(2)-binding affinity of human SBP [10].
• DLC-1 mRNA expression in cells with or without treatment with 5-aza-deoxycytidine (5-aza-CdR) or trichostatin A (TSA) was investigated by real-time RT-PCR [12].

Other interactions of DLEC1

• The smallest region homozygously deleted in 3p21.3T was flanked by D3S1298 and NL1-024 (D3S4285), excluding DLEC1 and MYD88 as candidate TSGs involved in cervical carcinogenesis [13].
• Candidate tumor-suppressor gene DLEC1 is frequently downregulated by promoter hypermethylation and histone hypoacetylation in human epithelial ovarian cancer [3].
• In addition, 80% of ovarian cancer cell lines significantly upregulated DLEC1 transcripts after histone deacetylase inhibitor treatment [3].

Analytical, diagnostic and therapeutic context of DLEC1

• By site-directed mutagenesis, we have identified several amino acid residues on cten and DLC-1 that are essential for this interaction [4].
• The methylation of the candidate tumor suppressor gene DLC-1 was detected in a high proportion of primary tumor and plasma DNA samples by using quantitative methylation-specific PCR analysis [7].
• METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect DLC-1 transcripts in RPMI 8226, U266, OPM-2 and XG-2 cell lines [12].

References