Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatocellular carcinoma (HCC) is a major malignancy in many parts of the world, especially in Asia and Africa. Loss of heterozygosity (LOH) on the long arm of chromosome 13 has been reported in HCC. In search of tumor suppressor genes in this region, here we have identified DLC2 (for deleted in liver cancer 2) at 13q12.3 encoding a novel Rho family GTPase-activating protein (GAP). DLC2 mRNA is ubiquitously expressed in normal tissues but was significantly underexpressed in 18% (8/45) of human HCCs. DLC2 is homologous to DLC1, a previously identified tumor suppressor gene at 8p22-p21.3 frequently deleted in HCC. DLC2 encodes a novel protein with a RhoGAP domain, a SAM (sterile alpha motif) domain related to p73/p63, and a lipid-binding StAR-related lipid transfer (START) domain. Biochemical analysis indicates that DLC2 protein has GAP activity specific for small GTPases RhoA and Cdc42. Expression of the GAP domain of DLC2 sufficiently inhibits the Rho-mediated formation of actin stress fibers. Introduction of human DLC2 into mouse fibroblasts suppresses Ras signaling and Ras-induced cellular transformation in a GAP-dependent manner. Taken together, our findings suggest a role for DLC2 in growth suppression and hepatocarcinogenesis.
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PMID:Deleted in liver cancer (DLC) 2 encodes a RhoGAP protein with growth suppressor function and is underexpressed in hepatocellular carcinoma. 1253 87

The deleted in liver cancer 2 (DLC2) gene, located at chromosome 13q12.3, is a recently identified tumor suppressor gene. The gene is frequently underexpressed in human hepatocellular carcinoma, and its chromosomal region shows frequent deletion. DLC2 encodes a unique RhoGTPase-activating protein (RhoGAP) specific for small RhoGTPases, RhoA, and Cdc42. With bioinformatic analysis, we have identified four different isoforms of DLC2, which we named DLC2alpha, DLC2beta, DLC2gamma, and DLC2delta. Three of the isoforms contain the RhoGAP domain, namely, DLC2alpha, DLC2beta, and DLC2gamma. Ectopic expression of these three isoforms in mouse fibroblasts showed cytoplasmic localization. Of interest, overexpression of these isoforms suppressed the lysophosphatidic acid-induced stress fiber formation in mouse fibroblasts and changed the morphology of the transfected cells from angular and spindle to round. Furthermore, the RhoA pull-down assay demonstrated a remarkable reduction in RhoA activity in the DLC2 transiently transfected cells. In contrast, cells transfected with inactive DLC2 GAP-mutant remained unchanged in cell morphology, actin stress fiber formation, and RhoA activity. HepG2 hepatoma cells stably transfected with the DLC2gamma isoform also changed to a round morphology, as in mouse fibroblasts. Of significance, these DLC2gamma stable transfectants showed marked suppression in cell proliferation, motility, and transformation, and there was a remarkable reduction in in vivo RhoA activity in these cells. These results suggest that DLC2 exhibits its tumor suppressor functions in vivo as a GAP specific for RhoA, exerting its effects in suppression of cytoskeleton reorganization, cell growth, cell migration, and transformation.
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PMID:Deleted in liver cancer 2 (DLC2) suppresses cell transformation by means of inhibition of RhoA activity. 1621 26

The deleted in liver cancer 2 (DLC2) is a tumor suppressor gene, frequently found to be underexpressed in hepatocellular carcinoma. DLC2 is a multidomain protein containing a sterile alpha-motif (SAM) domain, a GTPase-activating protein (GAP) domain, and a lipid-binding StAR-related lipid-transfer (START) domain. The SAM domain of DLC2, DLC2-SAM, exhibits a low level of sequence homology (15-30%) with other SAM domains, and appears to be the prototype of a new subfamily of SAM domains found in DLC2-related proteins. In the present study, we have determined the three-dimensional solution structure of DLC2-SAM using NMR methods together with molecular dynamics simulated annealing. In addition, we performed a backbone dynamics study. The DLC2-SAM packed as a unique four alpha-helical bundle stabilized by interhelix hydrophobic interactions. The arrangement of the four helices is distinct from all other known SAM domains. In contrast to some members of the SAM domain family which form either dimers or oligomers, both biochemical analyses and rotational correlation time (tau(c)) measured by backbone 15N relaxation experiments indicated that DLC2-SAM exists as a monomer in solution. The interaction of DLC2-SAM domain with sodium dodecyl sulfate (SDS) micelles and 1,2-dimyristoyl-sn-glycerol-3-phosphatidylglycerol (DMPG) phospholipids was examined by CD and NMR spectroscopic techniques. The DLC2-SAM exhibits membrane binding properties accompanied by minor loss of the secondary structure of the protein. Deletion studies showed that the self-association of DLC2 in vivo does not require SAM domain, instead, a protein domain consisting of residues 120-672 mediates the self-association of DLC2.
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PMID:Solution structures, dynamics, and lipid-binding of the sterile alpha-motif domain of the deleted in liver cancer 2. 1738 May 10

DLC2 (deleted in liver cancer 2), a Rho GTPase-activating protein, was previously shown to be underexpressed in human hepatocellular carcinoma and has tumor suppressor functions in cell culture models. We generated DLC2-deficient mice to investigate the tumor suppressor role of DLC2 in hepatocarcinogenesis and the function of DLC2 in vivo. In this study, we found that, unlike homologous DLC1, which is essential for embryonic development, DLC2 was dispensable for embryonic development and DLC2-deficient mice could survive to adulthood. We also did not observe a higher incidence of liver tumor formation or diethylnitrosamine (DEN)-induced hepatocarcinogenesis in DLC2-deficient mice. However, we observed that DLC2-deficient mice were smaller and had less adipose tissue than the wild type mice. These phenotypes were not due to reduction of cell size or defect in adipogenesis, as observed in the 190B RhoGAP-deficient mouse model. Together, these results suggest that deficiency in DLC2 alone does not enhance hepatocarcinogenesis.
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PMID:Deleted in liver cancer 2 (DLC2) was dispensable for development and its deficiency did not aggravate hepatocarcinogenesis. 1966 31