Deleted in liver cancer (DLC) 2 encodes a RhoGAP protein with growth suppressor function and is underexpressed in hepatocellular carcinoma.
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.
Ching
Yick-Pang
YP
Institute of Molecular Biology, University of Hong Kong, China.
Wong
Chun-Ming
CM
Chan
Shing-Fai
SF
Leung
Thomas Ho-Yin
TH
Ng
David Chi-Heng
DC
Jin
Dong-Yan
DY
Ng
Irene Oi-lin
IO
D016475:3T3 Cells; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D002471:Cell Transformation, Neoplastic; D002882:Chromosomes, Human, Pair 13; D005260:Female; D020690:GTPase-Activating Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D016147:Genes, Tumor Suppressor; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D019656:Loss of Heterozygosity; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000502:physiology
D020690:GTPase-Activating Proteins; D025521:Tumor Suppressor Proteins; C473606:Stard13 protein, mouse; C473607:STARD13 protein, human; C085379:rho GTPase-activating protein