Gankyrin: A potential target for drug therapy against hepatocellular carcinoma
- 1 Department of Biotechnology, University Institute of Engineering and Technology, Panjab University, Chandigarh, India
- 2 Center for System Biology and Bioinformatics, U.I.E.A.S.T, Panjab University, Chandigarh, India
- 3 Department of Biotechnology, University Institute of Engineering and Technology, Panjab University, Chandigarh, India
Abstract
Hepatocellular Carcinoma is a primary malignant tumor of the liver and gankyrin is an oncoprotein over-expressed in hepatocellular carcinoma. It has been found that Gankyrin protein reduces the level of p53 protein by increasing its ubiquitylation and degradation, following a MDM-2 mediated pathway. Interaction of gankyrin with MDM2 enhances the ubiquitylation of p53. Independent study of this protein molecule revealed that it is identical to the p28 subunit of the 26S proteasome, having seven similar alpha helical ankyrin repeats. Gankyrin also binds to the Tumor Suppressor Protein (TSP) Retinoblastoma (RB), thereby accelerating its phosphorylation and proteasomal degradation. Blocking the expression of Gankyrin with MDM2 in cases of Hepatocellular Carcinoma (HCC) promoted apoptosis in cancer cells. Hence, Gankyrin can be used as a potential target for drug therapy against Hepatocellular Carcinoma.
- erman J. J. (2004) Tumor taxanomy for the developmental classification of neoplasms. BMC Cancer, 4, 88-93. doi:10.1186/1471-2407-4-88.
- Thomas M. B. (2005) Hepatocellular Carcinoma: The need for progress. J Clin Oncol, 23, 2892-2899. doi:10.1200/JCO.2005.03.196.
- Quelle D.E., Zindy F., Ashmun R. A., and Sherr C. J. (1995) Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell, 83, 993–1000. doi:10.1016/0092-8674(95)90214-7.
- Iwakuma T. and Lozano G. (2003) MDM2, an introduction. Mol Cancer Res, 1, 993–1000. PMID:14707282 doi:10.1158/1541-7786
- Ieta K., Ojima E., Tanaka F., Nakamura Y., Haraguchi N., Mimori K., Inoue H., Kuwano H. and Mori M. (2007) Identification of overexpressed genes in hepatocellular carcinoma, with special reference to ubiquitin-conjugating enzyme E2C gene expression. Int. J. Cancer, 121, 33–38. doi:10.1002/ijc.22605.
- Higashitsuji H., Itoh K., Nagao T., Dawson S., Nonoguchi K., Kido T., Mayer R.J., Arii S., and Fujita J. (2000) Reduced stability of retinoblastoma protein by gankyrin, an oncogenic ankyrin-repeat protein overexpressed in hepatomas. Nat Med, 6, 96-99. doi:10.1038/71600
- Manjasetty B. A., Quedenau C., Sievert V., Büssow C., Niesen F., Delbrück H. and Heinemann U. (2004) X-Ray structure of Human Gankyrin, the product of a gene linked to Hepatocellular Carcinoma. PROTEINS: Structure, Function and Bioinformatics, 55, 14-217. doi:10.1002/prot.20028
- Hori T., Kato S., Saeki M., DeMartino G. N., Slaughter C.A., Takeuchi J., Tohe A., and Tanaka K. (1998) cDNA cloning and functional analysis of p28 (Nas6p) and p40.5 (Nas7p), two novel regulatory subunits of the 26S proteasome. Gene, 216, 113-122. doi:10.1016/S0378-1119(98)00309-6
- Higashitsuji H., Higashitsuji H., Itoh K., Sakurai T., Nagao, T., Sumitomo H., Masuda T., Dawson S., Shimada Y., Mayer R.J., and Fujita J. (2005) The oncoprotein gankyrin binds to MDM2/HDM2, enhancing ubiquitylation and degradation of p53. Cancer Cell, 8, 75-87. doi:10.1016/j.ccr.2005.06.006
- Li H., Fu X., Chen Y., Hong Y., Tan Y., Cao H., Wu M., and Wang H. (2005) Use of adenovirus-delivered siRNA to target oncoprotein p28GANK in hepatocellular carcinoma. Gastroenterology, 128, 2029-2041. doi:10.1053/j.gastro.2005.03.001.
- Nagao T., Higashitsuji H., Nonoguchi K., Sakurai T., Dawson S., Mayer R.J., Itoh K., and Fujita J. (2003) MAGE-A4 interacts with the liver oncoprotein gankyrin and suppresses its tumorigenic activity. J Biol Chem, 278, 10668-10674. doi:10.1074/jbc.M206104200