Discovery of a small-molecule binder of the oncoprotein gankyrin that modulates gankyrin activity in the cell

Chattopadhyay, Anasuya; O'Connor, Cornelius J.; Zhang, Fengzhi; Galvagnion, Céline; Galloway, Warren R. J. D.; Tan, Yaw Sing; Stokes, Jamie E.; Rahman, Taufiq; Verma, Chandra; Spring, David R.; Itzhaki, Laura S.

doi:10.1038/srep23732

Cited by 32 publications

(23 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Small molecule inhibitors and synthetic proteins inhibiting Gankyrin and restoring p53 levels in cells have been discovered and are possible candidates for further development. 120,121 A small molecule inhibitor called cjoc42 was shown to bind to the protein-protein interaction surface of PSMD10, preventing its interaction with 19S proteasome component ATPase S6 (PSMC4). 120 This blocked interaction leads to stabilization of wild-type p53 protein in osteosarcoma cells overexpressing PSMD10, when these cells are treated with cjoc42, probably because of interference with the delivery of p53 to proteasome for degradation.…”

Section: Therapeutic Perspectivesmentioning

confidence: 99%

“…120,121 A small molecule inhibitor called cjoc42 was shown to bind to the protein-protein interaction surface of PSMD10, preventing its interaction with 19S proteasome component ATPase S6 (PSMC4). 120 This blocked interaction leads to stabilization of wild-type p53 protein in osteosarcoma cells overexpressing PSMD10, when these cells are treated with cjoc42, probably because of interference with the delivery of p53 to proteasome for degradation. A synthetic artificial protein is an alternative for blockade of the large PSMD10 protein-protein interaction surface, if it can be successfully delivered to cells in vivo.…”

Section: Therapeutic Perspectivesmentioning

confidence: 99%

See 1 more Smart Citation

Proteasome expression and activity in cancer and cancer stem cells

Voutsadakis

2017

Tumour Biol.

View full text Add to dashboard Cite

Proteasome is a multi-protein organelle that participates in cellular proteostasis by destroying damaged or short-lived proteins in an organized manner guided by the ubiquitination signal. By being in a central place in the cellular protein complement homeostasis, proteasome is involved in virtually all cell processes including decisions on cell survival or death, cell cycle, and differentiation. These processes are important also in cancer, and thus, the proteasome is an important regulator of carcinogenesis. Cancers include a variety of cells which, according to the cancer stem cell theory, descend from a small percentage of cancer stem cells, alternatively termed tumor-initiating cells. These cells constitute the subsets that have the ability to propagate the whole variety of cancer and repopulate tumors after cytostatic therapies. Proteasome plays a role in cellular processes in cancer stem cells, but it has been found to have a decreased function in them compared to the rest of cancer cells. This article will discuss the transcriptional regulation of proteasome sub-unit proteins in cancer and in particular cancer stem cells and the relationship of the proteasome with the pluripotency that is the defining characteristic of stem cells. Therapeutic opportunities that present from the understanding of the proteasome role will also be discussed.

show abstract

Section: Therapeutic Perspectivesmentioning

confidence: 99%

Section: Therapeutic Perspectivesmentioning

confidence: 99%

Proteasome expression and activity in cancer and cancer stem cells

Voutsadakis

2017

Tumour Biol.

View full text Add to dashboard Cite

show abstract

“…We have reported that translational activity of CUGBP1 is involved in repression of p53 and p21 genes during diethylnitrosamine (DEN)-mediated cancer (16,24), suggesting that CUGBP1 promotes liver cancer through its translational activity. We also found that phosphorylation of CUGBP1 at Ser302 is changed after DEN treatments (25). To test the role of translational activity of CUGBP1 in cancer, we generated CUGBP1-S302A knock-in mice.…”

Section: Resultsmentioning

confidence: 99%

“…ChIP studies showed that the CUGBP1-dependent C/EBP␤-HDAC1 complexes occupy the Gank promoter and partially repress Gank. Our work is clinically important, since a recent paper has identified a small drug (cjoc42) which inhibits activities of Gank (25). Therefore, future studies will show if the…”

Section: Discussionmentioning

confidence: 99%

RNA Binding Protein CUGBP1 Inhibits Liver Cancer in a Phosphorylation-Dependent Manner

Lewis

Valanejad

Cast

et al. 2017

Molecular and Cellular Biology

View full text Add to dashboard Cite

Despite intensive investigations, mechanisms of liver cancer are not known. Here, we identified an important step of liver cancer, which is the neutralization of tumor suppressor activities of an RNA binding protein, CUGBP1. The translational activity of CUGBP1 is activated by dephosphorylation at Ser302. We generated CUGBP1-S302A knock-in mice and found that the reduction of translational activity of CUGBP1 causes development of a fatty liver phenotype in young S302A mice. Examination of liver cancer in diethylnitrosamine (DEN)-treated CUGBP1-S302A mice showed these mice develop much more severe liver cancer that is associated with elimination of the mutant CUGBP1. Searching for mechanisms of this elimination, we found that the oncoprotein gankyrin (Gank) preferentially binds to and triggers degradation of dephosphorylated CUGBP1 (de-ph-S302-CUGBP1) or S302A mutant CUGBP1. To test the role of Gank in degradation of CUGBP1, we generated mice with liver-specific deletion of Gank. In these mice, the tumor suppressor isoform of CUGBP1 is protected from Gank-mediated degradation. Consistent with reduction of CUGBP1 in animal models, CUGBP1 is reduced in patients with pediatric liver cancer. Thus, this work presents evidence that de-ph-S302-CUGBP1 is a tumor suppressor protein and that the Gank-UPS-mediated reduction of CUGBP1 is a key event in the development of liver cancer. KEYWORDS CUGBP1, HCC, HBL, gankyrin, C/EBP␤, phosphorylation, C/EBP Q uiescent livers express up to 20 tumor suppressor proteins (1); however, they are eliminated by different mechanisms under conditions of liver cancer. Liver cancer remains the fifth most common cancer and the third most common cause of cancerrelated death in the world (2). The mechanisms of cancer-related elimination or reduction of tumor suppressor proteins include transcriptional repression of the genes, degradation of proteins, and posttranslational modifications that change biological activities of these proteins (1, 3, 4). A number of recent papers showed that certain proteins work as oncoproteins and as tumor suppressors depending on cell environment, target genes, and posttranslational modifications (5-12). In this regard, Dreijerink et al. have recently shown that menin tumor suppressor protein displays its tumor suppression activity in a variety of cancer cells; however, it possesses oncogenic activities in breast tumorigenesis (5). Another recent report revealed that the Kruppelassociated box zinc finger protein ZNF224 can behave as an oncoprotein and as a tumor suppressor protein and that these opposite activities of ZNF224 are controlled by specific protein-protein interactions (6). In addition to the opposite changes of the activities of tumor suppressor proteins and oncogenes, certain microRNAs display cell type-specific oncogenic or tumor suppression activities. Hickey et al. recently demon-

show abstract

“…These small molecule inhibitors have been designed based on the crystal structure of Gankyrin and the main function of this molecule was reduction or suppression of the binding ability of Gankyrin towards its partners [43]. A newly discovered small molecule named cjoc42 was introduced as the first small molecule capable of binding and inhibiting human Gankyrin [112]. Cjoc42 designed base on existence of ankyrin repeat sequence in Gankyrin that is important to protein-protein interactions.…”

Section: Inhibitory Protein-based Approachesmentioning

confidence: 99%

Gankyrin: a novel promising therapeutic target for hepatocellular carcinoma

Zamani

Riahi

Momtazi‐Borojeni

et al. 2017

Artificial Cells, Nanomedicine, and Biotechnology

View full text Add to dashboard Cite

Hepatocellular carcinoma (HCC) is known as fifth common malignancies and third common cause of cancer-related death worldwide. The identification of various mechanisms which are involved in hepatocarcinogenesis contributes in finding a variety of cellular and molecular targets for HCC diagnosis, prevention and therapy. Among various identified targets in HCC pathogenesis, Gankyrin is a crucial oncoprotein that is up-regulated in HCC and plays a pivotal role in the initiation and progression of the HCC. Oncogenic role of Gankyrin has been found to stem from inhibition of two ubiquitous tumour suppressor proteins, retinoblastoma protein (pRb) and P53, and also modulation of several vital cellular signalling pathways including Wnt/β-Catenin, NF-κB, STAT3/Akt, IL-1β/IRAK-1 and RhoA/ROCK. As a result, Gankyrin can be considered as a potential candidate for diagnosis and treatment of HCC. In this review, we summarized the physiological function and the significant role of Gankyrin as an important therapeutic target in HCC.

show abstract

Discovery of a small-molecule binder of the oncoprotein gankyrin that modulates gankyrin activity in the cell

Cited by 32 publications

References 32 publications

Proteasome expression and activity in cancer and cancer stem cells

Proteasome expression and activity in cancer and cancer stem cells

RNA Binding Protein CUGBP1 Inhibits Liver Cancer in a Phosphorylation-Dependent Manner

Gankyrin: a novel promising therapeutic target for hepatocellular carcinoma

Contact Info

Product

Resources

About