Gankyrin oncoprotein overexpression as a critical factor for tumor growth in human esophageal squamous cell carcinoma and its clinical significance

Ortiz, Cristián; Ito, Takahiro; Tanaka, Eiji; Tsunoda, Shigeru; Nagayama, Satoshi; Sakai, Yoshiharu; Higashitsuji, Hiroaki; Fujita, Jun; Shimada, Yutaka

doi:10.1002/ijc.23106

Cited by 44 publications

(42 citation statements)

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“…1, C and D). Ankyrin repeats are a conserved sequence of 33 amino acids found in many proteins with a wide variety of functions, ranging from cell cycle control, transcription regulation, and cell differentiation, to cell anchorage (37)(38)(39). One ankyrin repeat consists of a ␤-hairpin loop and two ␣-helices.…”

Section: Discussionmentioning

confidence: 99%

“…For example, p16 not only binds to Cdk4 and Cdk6, but also to transcription factor NF-B and c-Jun kinase under physiological conditions (40,41). Another example of the multipartner ankyrin protein is gankyrin, which is overexpressed in esophageal carcinoma and hepatoma (39). Its physiological partners include Cdk4, Rb, and S6 ATPase of the 26 S proteasome and HDM2 (42,43).…”

Section: Discussionmentioning

confidence: 99%

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Identification and Functional Analysis of a Novel Cyclin E/Cdk2 Substrate Ankrd17

Deng

Ballif

et al. 2009

Journal of Biological Chemistry

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Cyclin E/Cdk2 is a key regulator in G 1 -S transition. We have identified a novel cyclin E/Cdk2 substrate called Ankrd17 (ankyrin repeat protein 17) using the TAP tag purification technique. Ankrd17 protein contains two clusters of a total 25 ankyrin repeats at its N terminus, one NES (nuclear exporting signal) and one NLS (nuclear localization signal) in the middle, and one RXL motif at its C terminus. Ankrd17 is expressed in various tissues and associates with cyclin E/Cdk2 in an RXL-dependent manner. It can be phosphorylated by cyclin E/Cdk2 at 3 phosphorylation sites (Ser 1791 , Ser 1794 , and Ser 2150 ). Overexpression of Ankrd17 promotes S phase entry, whereas depletion of Ankrd17 expression by small interfering RNA inhibits DNA replication and blocks cell cycle progression as well as up-regulates the expression of p53 and p21. Ankrd17 is localized to the nucleus and interacts with DNA replication factors including MCM family members, Cdc6 and PCNA. Depletion of Ankrd17 results in decreased loading of Cdc6 and PCNA onto DNA suggesting that Ankrd17 may be directly involved in the DNA replication process. Taken together, these data indicate that Ankrd17 is an important downstream effector of cyclin E/Cdk2 and positively regulates G 1 /S transition.Progression through the cell cycle is driven by the sequential and periodic activation of cyclin/Cdk complexes. Cyclin D/Cdk4/6 4 complexes are active throughout the G 1 phase, cyclin E/Cdk2 at the G 1 /S boundary, cyclin A/Cdk2 during S phase, and cyclin A/Cdk1 and cyclin B/Cdk1 during the G 2 /M transition. Cyclin E/Cdk2 plays a central role in coordinating both the onset of S phase and centrosome duplication in cell cycle (1-4). It presumably exerts most of its biologic activities by phosphorylating its substrates, most frequently through the RXL motif in the substrate that interacts with the cyclin box (5-8). A number of RXL-containing proteins are themselves cell cycle regulatory proteins. In the case of pRb, cyclin E/Cdk2-mediated Rb phosphorylation inactivates Rb by derepressing E2F transcription factors (9, 10), whereas in the case of p27, phosphorylation of p27 by cyclin E/Cdk2 stimulates its degradation by the SCF-Skp2 ubiquitin ligase (11-15).There are a number of proteins identified as cyclin E/Cdk2 substrates that regulate cell division. NPAT is a transcription factor that controls cell cycle-dependent histone gene transcription. The phosphorylation of NPAT by cyclin E/Cdk2 promotes histone transcription (16 -19). Cells without NPAT fail to enter S phase from quiescence (20). CBP/p300 is another protein phosphorylated by cyclin E/Cdk2 at G 1 /S transition to activate its histone acetyltransferase activity (21) and may function as a cofactor for many transcription factors including E2F (22). Interestingly, cyclin E/Cdk2 phosphorylates E2F-5 and increases its transcriptional activity through CBP/p300 recruitment (23). Cyclin E/Cdk2 also phosphorylates centrosomal proteins that regulate centrosome duplication. Phosphorylation of nucleophosmin (NPM) by cyc...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identification and Functional Analysis of a Novel Cyclin E/Cdk2 Substrate Ankrd17

Deng

Ballif

et al. 2009

Journal of Biological Chemistry

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“…The expression of Gankyrin has been investigated in a variety of cancers with nearly universal findings that showed elevated protein and/or mRNA levels in cancers when compared with normal counterparts (4)(5). Gankyrin has been shown to be involved in carcinogenesis and oncogene-induced tumor onset and progression (4,(6)(7)(8)(9)(10). Overexpression of Gankyrin promotes cellular proliferation by targeting retinoblastoma protein (Rb), leading to subsequent Rb degradation, activation of E2F transcription factor, and DNA synthesis of genes required for G 1 -S-phase transition (11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Gankyrin Activates IL-8 to Promote Hepatic Metastasis of Colorectal Cancer

Bai

Tai

et al. 2013

Cancer Research

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Hepatic metastasis is responsible for the majority of colorectal cancer (CRC)-related mortalities. Although Gankyrin (PSMD10) has been implicated in cancer metastasis, its exact role and underlying mechanisms of CRC hepatic metastasis remain largely unknown. Herein, we showed that the expression of Gankyrin was higher in primary CRC with hepatic metastasis compared with CRC without metastasis. RNAi-mediated silencing of Gankyrin expression in highly metastatic human CRC cells impaired their migratory and metastatic capacity in vivo. Genome-wide transcriptome profiling revealed activation of the interleukin (IL)-8 signaling pathway by Gankyrin. Protein levels of IL-8 and cyclin D1 (CCND1), the two important molecules in the IL-8 pathway, were positively correlated with Gankyrin expression in human CRC specimens. Furthermore, genetic deletion of cyclin D1 showed its requirement in Gankyrin-mediated cell migration. Finally, administration of recombinant IL-8 rescued the migratory defect of CRC cells where Gankyrin expression was silenced. Together, our findings highlight the importance of Gankyrin in hepatic metastasis of CRC and point out its candidature as a potential prognostic marker and therapeutic target to improve the clinical management of metastatic CRC. Cancer Res; 73(14); 4548-58. Ó2013 AACR.

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“…Then, a flow cytrometric assay was performed to evaluate the cell cycle phase distribution, as previously described27. The evaluation of DNA content was performed using a FACScan flow cytometer (Becton Dickinson, Mountain View, CA).…”

Section: Methodsmentioning

confidence: 99%

Gradually elevated expression of Gankyrin during human hepatocarcinogenesis and its clinicopathological significance

Jing

Zhang

Meng³

et al. 2014

Sci Rep

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Gankyrin is an important oncoprotein that is overexpressed in human hepatocellular carcinoma (HCC). However, the gradual alteration of Gankyrin in successive stages during human HCC development and the mechanism of Gankyrin-mediated hepatocarcinogenesis remain largely unknown. In this study, we evaluated the pattern and level of Gankyrin protein expression using immunohistochemistry in various liver tissues, including normal liver, chronic hepatitis, cirrhosis, adenomatous hyperplasia (AH), and HCC tissues, to analyze its clinicopathological significance. Furthermore, we stably transfected the shRNA-Gan vector, which targets human Gankyrin, into HepG2 cells to assess the role of Gankyrin in cell proliferation and tumorigenicity. The expression level of Gankyrin in the cytoplasm, nucleus, and whole cell was gradually elevated during consecutive stages of hepatocarcinogenesis. The nuclear Gankyrin level in AH was significantly higher than that in normal liver, chronic hepatitis, and cirrhotic tissues. The cytoplasmic, nuclear, and total cellular Gankyrin expression levels in HCC were significantly correlated with capsular invasion and intrahepatic metastasis. Silencing Gankyrin expression using shRNA-Gan repressed tumor cell proliferation, tumorigenicity, migration, and invasion in vitro. Our findings demonstrate that Gankyrin is aberrantly expressed beginning at the initiation stage and plays an important role in the initiation, promotion, and progression of hepatocarcinogenesis.

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Gankyrin oncoprotein overexpression as a critical factor for tumor growth in human esophageal squamous cell carcinoma and its clinical significance

Cited by 44 publications

References 44 publications

Identification and Functional Analysis of a Novel Cyclin E/Cdk2 Substrate Ankrd17

Identification and Functional Analysis of a Novel Cyclin E/Cdk2 Substrate Ankrd17

Gankyrin Activates IL-8 to Promote Hepatic Metastasis of Colorectal Cancer

Gradually elevated expression of Gankyrin during human hepatocarcinogenesis and its clinicopathological significance

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