Disease relevance of PSMD10

• Gankyrin is an ankyrin repeat oncoprotein commonly overexpressed in hepatocellular carcinomas [1].
• Previous studies identified gankyrin as a component of the 26S proteasome that is consistently overexpressed in liver cancer and promotes cell transformation by binding RB [2].
• Transduction with a HIV Tat-MAGE-A4DeltaN1 fusion protein suppressed anchorage-independent growth of gankyrin-overexpressing cells in vitro and in vivo [3].
• The newly discovered oncogenic protein gankyrin, which contains six ankyrin repeats, has been reported to be involved in the phosphorylation and degradation of the retinoblastoma gene product, Rb [4].
• We conclude that: 1) EIA testing and WB/RIPA verification identified 10 (0.025%) HTLV-1 infected individuals among 39,898 low-risk blood donors; 2) anti-p24 may be a more sensitive and specific indicator of HTLV-1 infection than antibodies to p19, p28, or p53/55; and 3) presently, both WB and RIPA are needed to verify HTLV-1 EIA reactivity [5].

High impact information on PSMD10

• The expression of gankyrin was increased in all 34 hepatocellular carcinomas studied [6].
• These results demonstrate the importance of ubiquitin-proteasome pathway in the regulation of cell growth and oncogenic transformation, and indicate that gankyrin overexpression contributes to hepatocarcinogenesis by destabilizing RB1 [6].
• Gankyrin induced anchorage-independent growth and tumorigenicity in NIH/3T3 cells [6].
• Here, we discuss the activities of gankyrin and present a model for its function in the regulation of pRb and p53 [7].
• In conclusion, gankyrin is a small versatile cell cycle regulator that illustrates the essential interplay between the ubiquitin proteasome system and gene expression in the cell [7].

Chemical compound and disease context of PSMD10

• The main protein of the core of murine mammary tumor virus, with a molecular weight of 28,000 (p28), was solubilized by deoxycholate treatment of the virus and purified by Ultrogel ACA-54 filtration and hydroxyapatite chromatography [8].

Biological context of PSMD10

• Gankyrin is a 25-kDa hepatocellular carcinoma-associated protein that mediates protein-protein interactions in cell cycle control and protein degradation [9].
• Deletional mutagenesis shows that the C-terminal 78 amino acids of the S6 ATPase are necessary and sufficient to mediate the interaction with gankyrin [10].
• Downregulation of gankyrin induces apoptosis in cells with wild-type p53 [1].
• Downregulation of gankyrin reduced amounts of Mdm2 and p53 associated with the 26S proteasome [1].
• Gankyrin also binds to CDK4 and the tumor suppressor RB, and accelerates phosphorylation and proteasomal degradation of RB [11].

Anatomical context of PSMD10

• 28,000-dalton polypeptide (p28) of adult T-cell leukemia-associated antigen encoded by 24 S mRNA of human T-cell leukemia virus has an associated protein kinase activity [12].
• In contrast, the expression of p28/gankyrin mRNA was intensively detected in all 5 hepatoma cell lines tested, markedly increased in 57 of 64 and moderately increased in 5 of 64 HCC samples [13].
• The overexpression of p28/gankyrin protein in HCC was targeted in hepatic tumor cells, not in bile duct cells and other interstitial cells [13].
• In addition, p28/gankyrin mRNA expression level was higher in HCC with portal vein tumor thrombus and microscopic hepatic vein involvement (P=0.021 and P=0.047, respectively) [13].
• BACKGROUND: Human gankyrin gene product (p28GANK) is a novel oncogenic protein ubiquitously overexpressed in hepatocellular carcinoma and also plays a role in cell cycle progression in normal hepatocytes and liver regeneration [14].

Associations of PSMD10 with chemical compounds

• The phosphokinase activity of p28 was specific to the serine residue but was not to the tyrosine residue [12].
• Gankyrin has been crystallized from polyethylene glycol solutions and diffraction data have been obtained from these crystals that extend to 2.1 A spacing [15].
• The isozyme form of eukaryotic initiation factor 4F [eIF-(iso)4F] from wheat germ is composed of a p28 subunit that binds the 7-methylguanine cap of mRNA and a p86 subunit having unknown function [16].
• Gel filtration column chromatography of unreduced p28 in the presence of 0.5% NP-40 or 0.1% deoxycholate gave elution characteristics consistent with a m.w. of approximately 60,000 to 100,000 [17].
• Protein p28 was prominently represented in plasma membranes isolated on discontinuous sucrose density gradients and was identified as a cell surface glycoprotein based on studies in which intact stimulated cells were exposed to degradative enzymes [18].

Physical interactions of PSMD10

• In the current issue of Cancer Cell, Fujita and colleagues (Higashitsuji et al., 2005) show that gankyrin also binds MDM2 and facilitates its destruction of p53 [2].

Regulatory relationships of PSMD10

• The proteasomal ATPases are part of the AAA (ATPases associated with diverse cellular activities) family, members of which are molecular chaperones; gankyrin complexes may therefore influence CDK4 function during oncogenesis [10].
• The oncoprotein gankyrin negatively regulates both p53 and RB by enhancing proteasomal degradation [11].

Other interactions of PSMD10

• Gankyrin interacts with both free and regulatory complex-associated S6 ATPase and is not stably associated with the 26 S particle [10].
• It reveals that the entire 226-residue gankyrin polypeptide folds into seven ankyrin repeat elements [9].
• We further demonstrated a different mechanism for gankyrin to facilitate the phosphorylation of Rb, by binding with cyclin-dependent kinase 4 (CDK4) [4].
• Identification of the p28 subunit of eukaryotic initiation factor 3(eIF3k) as a new interaction partner of cyclin D3 [19].
• CONCLUSIONS: Sirpalpha1 might block the cell cycle of liver cancer, inhibit cell proliferation, promote cell apoptosis by decreasing the expression of cyclin D1, beta-catenin and gankyrin [20].

Analytical, diagnostic and therapeutic context of PSMD10

• Gankyrin, a recently discovered oncoprotein, is a promising target for drug therapy because it is overexpressed in most hepatocellular carcinomas [3].
• Crystallization of gankyrin, an oncoprotein that interacts with CDK4 and the S6b (rpt3) ATPase of the 19S regulator of the 26S proteasome [15].
• METHODS: 64 specimens of HCC and para-carcinoma tissues, 22 specimens of non-tumor liver tissues (7 normal, 15 cirrhosis), 10 specimens of normal human tissues and 5 hepatoma cell lines were studied for the expression of p28/gankyrin by Northern blot [13].
• Radioimmunoassay for protein p28 of murine mammary tumor virus in organs and serum of mice and search for related antigens in human sera and breast cancer extracts [8].
• Absorption and immunoprecipitation studies with alpha-ATC indicated that p28 was not present on erythrocytes, platelets, neutrophils, six B cell lines, six null cell lines, and seven other T lymphoblastoid cell lines [17].

References