Disease relevance of DLC1

• One of the genes from this region that is expressed by our suppressed hybrids is a candidate tumour suppressor gene, DLC1 (deleted in liver cancer), which has homology to rat RhoGAP [1].
• Evaluation of DLC1 as a prostate cancer susceptibility gene: mutation screen and association study [2].
• We also showed that down-regulation of DLC1 and Ciz1 reduced both Cdk2 activity and cell cycle progression of breast cancer ZR-75 and MCF-7 and endometrial Ishikawa cancer cells [3].
• To achieve this goal, we used human breast ductal carcinoma ZR-75 cells overexpressing DLC1 as a model system [3].
• DLC1 is unlikely to be a primary target for deletions on chromosome arm 8p22 in head and neck squamous cell carcinoma [4].
• We thus found frequent epigenetic silencing of DLC1 in NPC, esophageal and cervical carcinomas, and a high correlation of methylation with its downregulation, suggesting a predominant role of epigenetic inactivation [5].

High impact information on DLC1

• Circannual control of hibernation by HP complex in the brain [6].
• 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 [7].
• Unexpectedly, the interaction between DLC-1 and the cten SH2 domain is independent of tyrosine phosphorylation of DLC-1 [7].
• 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 [7].
• Furthermore, Dlc-1 and I kappaB alpha were found to associate with the microtubule organizing center, a perinuclear region from which microtubules radiate [8].

Chemical compound and disease context of DLC1

• Treatment with 5-aza-2'-deoxycytidine (5-Aza-dC) induced DLC-1 mRNA expression in the gastric cancer cell lines that have the methylated alleles [9].
• METHODS: Patients with active HP infection and peptic ulcer, a history of peptic ulcer, or nonulcer dyspepsia were randomized to either lansoprazole 30 mg b.i.d., clarithromycin 500 mg b.i.d., and metronidazole 500 mg b.i.d. or lansoprazole 30 mg b.i.d., clarithromycin 500 mg b.i.d., and bismuth subsalicylate 524 mg b.i.d. (LCB) for 7 days [10].
• In comparison with Fast Blue B and Fast Garnet GBC HP is a faster coupler, furnishes azodyes which are stable, amorphous (even without lipid extractions from sections), more substantive and in the case of 1-naphthylamine almost insoluble in ordinary lipid solvents used for the dehydration and clearing of sections before mounting [11].

Biological context of DLC1

• The delineation of the gene structure allows mutation analysis of DLC1 in other tumour types for which it remains a candidate tumour suppressor gene based on its location and homology to rhoGAP [1].
• The rarity of exonic missense mutations, and the absence of protein-truncating mutations, indicates that DLC1 is not the target of 8p LOH in colorectal or ovarian tumours [1].
• We have delineated the structure of the DLC1 gene and used single-stranded conformation polymorphism analysis (SSCP) to look for sequence variants in 126 colorectal and 33 ovarian primary tumours and cell lines [1].
• Seven informative SNPs that spanned the complete DLC1 gene were genotyped in an additional 249 sporadic cases and 222 unaffected controls [2].
• The 14-kDa dynein light chain-family protein Dlc1 is required for regular oscillatory nuclear movement and efficient recombination during meiotic prophase in fission yeast [12].

Anatomical context of DLC1

• However, there are no reports of DLC1 mutation screening in prostate tumors or in germ line DNA of prostate cancer patients [2].
• During meiotic prophase, Dlc1 was present along astral microtubules and microtubule-anchoring sites on the cell cortex, reminiscent of the cytoplasmic dynein heavy chain Dhc1 [12].
• Up-regulation of dynein light chain 1 (DLC1), a component of cytoskeleton signaling, was recently found to promote tumorigenesis [3].
• Our recent finding has revealed that inhibition of Rho-mediated actin stress fiber formation by DLC1 is associated with its growth inhibitory activity [13].
• Our findings presented here suggest a new model for the action of DLC1 in hepatocytes, whereby DLC1-tensin2 complex interacts with Rho GTPases in caveolae to effect cytoskeletal reorganization [13].

Associations of DLC1 with chemical compounds

• We identified KIBRA, a WW domain- and a glutamic acid stretch-containing protein, as a DLC1-binding protein and showed that it interacts with DLC1 both in vitro and in vivo [14].
• Transcriptional silencing of DLC-1 was primarily associated with aberrant DNA methylation, rather than genomic deletion as 5-aza-2'-deoxycytidine induced reactivation of DLC-1 expression in 82% (9/11) NSCLC cell lines showing downregulated DLC-1 [15].
• Pak1 phosphorylation of DLC1 on Ser-88 controls vesicle formation and trafficking functions, as Ser-88 substitution for alanine prevents macropinocytosis [16].
• Recent studies have identified dynein light chain-1 (DLC1), a component of the dynein motor, as a p21-activated kinase 1 (Pak1)-interacting substrate with binding sites mapped to amino acids 61-89 of DLC1 and phosphorylation site at serine 88 [16].
• Pak1 associates with the complex of DLC1 and BimL, a proapoptotic BH3-only protein, and phosphorylates both proteins [17].
• We further show that treatment of cells with phorbol ester or coexpression of 14-3-3 proteins, blocks DLC1 nucleocytoplasmic shuttling, probably by masking a previously unrecognized nuclear localization sequence [18].

Enzymatic interactions of DLC1

• DLC-1 (deleted in liver cancer) gene is frequently deleted in hepatocellular carcinoma [9].

Regulatory relationships of DLC1

• Deleted in liver cancer 1 (DLC1) is a recently identified tumor suppressor gene frequently underexpressed in hepatocellular carcinoma (HCC) [13].

Other interactions of DLC1

• In the present study, we aimed to characterize the tumor suppressor roles of DLC1 in hepatocellular carcinoma [19].
• Sequence analysis of DLC1 and tensin2 identified caveolin-1 binding motif in both proteins [13].
• We found that KIBRA-DLC1 complex is recruited to ER-responsive promoters [14].
• In addition, the CpG island 5' to the DLC-1 gene was methylated in 3 of 7 HCC cell lines and in 6 (24%) of 25 primary HCCs [20].
• Treatment of the three prostate carcinoma cell lines (PC-3, LNCaP, and 22Rv1) expressing a low level of DLC-1 transcripts with inhibitors of DNA methyltransferase or histone deacetylase increased DLC-1 expression [21].

Analytical, diagnostic and therapeutic context of DLC1

• Moreover, with real-time quantitative PCR, we found that DLC-1 mRNA was significantly underexpressed in HCCs when compared with the corresponding nontumorous livers (P < 0.0001) [20].
• Full-length cDNA for DLC-1 of 3800 bp encodes a protein of 1091 amino acids, has 86% homology with rat p122 RhoGAP gene, and was localized by fluorescence in situ hybridization on chromosome 8 at bands p21.3-22 [22].
• It was further evidenced by an aberrant DLC-1 promoter methylation pattern, which was detected by Southern blotting in 73% (8/11) of NSCLC cell lines with downregulation of the gene [15].
• EXPERIMENTAL DESIGN: Primary prostate carcinomas, prostate carcinoma cell lines, benign prostatic hyperplasias, and normal prostatic tissues were examined for detection of functional and structural alterations of the DLC-1 gene by real-time PCR, methylation-specific PCR, and Southern and Western blots [21].
• CONCLUSIONS: These results show that the transcriptional silencing of DLC-1 by two epigenetic mechanisms is common and may be involved in the pathogenesis of prostate carcinomas and benign prostatic hyperplasias and could have potential clinical application in the early detection and gene therapy of prostate cancer [21].

References