Cdc6 requires anchorage for its expression

Jinno, Shigeki; Sakurai-Yageta, Mika; Nagata, Akihisa; Okayama, Hiroto

doi:10.1038/sj.onc.1205249

Cited by 20 publications

(25 citation statements)

References 46 publications

(64 reference statements)

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“…Consistent with such a mechanism, there are multiple proteolytic systems that degrade Cdc6 when cells are forced to arrest proliferation. During G 1 arrest induced by growth factor withdrawal or anchorage loss, Cdc6 is degraded mainly by the APC/C CDH1 ubiquitin ligase but also by another ubiquitin ligase(s) yet to be identified and even likely by a lysosomal cysteine protease(s) (19,21,23). In addition, when cell DNA is damaged, Cdc6 is eliminated by the Huwe1 ubiquitin ligase (38).…”

Section: Discussionmentioning

confidence: 99%

“…Recently it was found that in fibroblasts activation of mTORC1 requires a signal for cell anchorage to the extracellular matrix, which is mediated by Rho-associated kinase, which directly inactivates Tsc2 by phosphorylating its Thr 1203 (21,22). When deprived of anchorage to the extracellular matrix, virtually all the cells constituting solid organs of animals arrest in G 1 with inactivation of both Cdk4/Cdk6 and Cdk2, facilitated degradation of Cdc6, and induction of apoptosis known as anoikis (23)(24)(25). Anchorage deprivation-induced mTORC1 inactivation is responsible for the inactivation of Cdk4/Cdk6 and the degradation of Cdc6, whereas similarly induced FADD-mediated caspase-8 activation is responsible for the initiation of anoikis at least in normal fibroblast and epithelial cells (21,26).…”

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confidence: 99%

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Cdc6 Protein Obstructs Apoptosome Assembly and Consequent Cell Death by Forming Stable Complexes with Activated Apaf-1 Molecules

Niimi

Arakawa-Takeuchi

Uranbileg

et al. 2012

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Cdc6 Protein Obstructs Apoptosome Assembly and Consequent Cell Death by Forming Stable Complexes with Activated Apaf-1 Molecules

Niimi

Arakawa-Takeuchi

Uranbileg

et al. 2012

Journal of Biological Chemistry

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“…Phosphorylation of Rb leads to activation of the E2F-DP1 transcriptional factor complex that controls the expression of genes essential for onset of the S phase (14). Although there appears to be cell type-and genotype-specific differences in the control of anchorage-dependent growth, a recent study has demonstrated that the G 1 Cdks and Cdc6 constitute major cell cycle targets for the regulation of the G 1 -S transition by anchorage and oncogenic stimulation (25). Gankyrin binds to Cdk4, evades inhibition by p16…”

Section: Discussionmentioning

confidence: 99%

MAGE-A4 Interacts with the Liver Oncoprotein Gankyrin and Suppresses Its Tumorigenic Activity

Nagao

Higashitsuji

Nonoguchi

et al. 2003

Journal of Biological Chemistry

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Hepatocellular carcinoma ranks among the most common malignancies in Southeast Asia and South Africa. Although there are many modalities of treatment, the recurrence and metastasis rates are high, and the prognosis is unsatisfactory. Gankyrin, a recently found oncoprotein, is a promising target for drug therapy because it is overexpressed in all studied hepatocellular carcinomas. Gankyrin contains six ankyrin repeats and interacts with Rb, Cdk4, and the S6 ATPase of the 26 S proteasome. In this study, a yeast two-hybrid screen with gankyrin has identified MAGE-A4 as another interacting protein. The interaction, mediated by the C-terminal half of MAGE-A4, was reproduced in mammalian cells. The interaction was specific to MAGE-A4, because other MAGE family proteins structurally similar to MAGE-A4, i.e. MAGE-A1, MAGE-A2, and MAGE-A12, did not bind to gankyrin. MAGE-A4 partially suppressed both anchorage-independent growth in vitro and tumor formation in athymic mice of gankyrin-overexpressing cells. The ability of mutant MAGE-A4 to interact with gankyrin correlated with the ability to suppress the anchorage-independent growth. These results demonstrate that MAGE-A4 binds to gankyrin and suppresses its oncogenic activity. So far, the major focus of studies on the MAGE proteins has been on their potential for cancer immunotherapy. Our results may also shed light on novel functions for MAGE-A proteins.Gankyrin (gann ankyrin repeat protein, also known as PSMD10 and p28) is an oncoprotein, the expression of which is increased (1, 2) in hepatocellular carcinomas (HCCs). 1Gankyrin consists of six ankyrin repeats and a 38-amino acid N-terminal extension and binds to the retinoblastoma tumor suppressor protein (Rb), the S6 ATPase subunit of the 26 S proteasome (PSMC4, RPT3, TBP7), and cyclin-dependent kinase 4 (Cdk4) (1, 3, 4). Overexpression of gankyrin increases both the phosphorylation and degradation of Rb in vivo and oncogenically transforms NIH/3T3 cells. Gankyrin binds to Cdk4 and counteracts the inhibitory function of the tumor suppressors p16INK4A and p18 INK4C (4). In a rodent model of hepatocarcinogenesis, gankyrin is overexpressed from the earliest stage of tumor development (5). These findings suggest that gankyrin is a major player in cell cycle control and tumorigenesis in HCCs.The MAGE (melanoma antigen) genes were initially identified because they encode tumor antigens that can be recognized by cytolytic T lymphocytes derived from the blood lymphocytes of cancer patients (6). The MAGE gene family is composed of more than 25 genes in humans and are classified as type I MAGE genes (including MAGE-A, MAGE-B, and MAGE-C genes) and type II MAGE genes, which include those that reside outside of the MAGE-A, MAGE-B, and MAGE-C genomic clusters (7, 8). The MAGE-A subfamily comprises 12 genes (MAGE-A1 to MAGE-A12), and is expressed in various types of tumors but not in normal adult tissues, except for testis and placenta. The MAGE-A antigens are of particular interest for antitumor immunotherapy because they are stri...

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“…One of the growth-suppressive conditions best suited to examine this correlation is culture in methylcellulose medium because, under this condition, any cells without the ability of anchorage-independent proliferation are forced to arrest in G 1 no matter how high growth stimulation is, due to anchorage lossimposed downregulation of Cdc6 (Jinno et al, 2002) and high induction of p27 KIP1 (Fang et al, 1996;Kawada et al, 1997). The Cdk6-D3 and Cdk6-D1 double overexpressors of BALB/c3T3 and the Cdk6-D3 double overexpressors of C3H10T1/2 were incubated in methylcellulose medium for 36 h to undergo arrest in G 1 and cell lysates were prepared.…”

Section: The Kinase Activity In Cdk6 Is Essential For Sensitization Omentioning

confidence: 99%

Overexpression of Cdk6–cyclin D3 highly sensitizes cells to physical and chemical transformation

et al. 2003

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Virtually all mammalian cells express two seemingly redundant cyclin-D-dependent kinases (Cdk4 and Cdk6) and three partner cyclins (D1, D2 and D3) essential for the G 1 -S transition, with predominant expression of Cdk4 and D1 in mesenchymal cells and Cdk6 and D3 in hematopoietic cells. We recently found two novel functions for Cdk6 executed in fibroblasts although unlike Cdk4 it is dispensable for their proliferation. In the rat fibroblast NRK-49F cells, oncogenic stimulation recruits Cdk6 to participate in a step of the cell cycle start that seems to be critical for anchorage-independent S-phase onset. Among the kinase-D-type cyclin combinations, the Cdk6-cyclin-D3 complex has a unique ability to evade inhibition by cyclin-dependent kinase inhibitors and thereby control the cell's proliferative competence under growth-suppressive conditions. We describe here that 2-5-fold overexpression of both Cdk6 and D3 enhances by 5 Â 10 3 -10 6 -fold the susceptibility of the BALB/c3T3 and C3H10T1/2 mouse fibroblast lines to ultraviolet irradiation-as well as 3-methylcholanthrene-induced transformation. This result suggests that deregulated expression of Cdk6 and cyclinD3 may predispose cells to malignant transformation, supporting the recent finding that cyclin D3 activated by chromosomal rearrangement is the causative gene of non-Hodgkin B lymphoma, in which Cdk6 is the major partner kinase.

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Cdc6 requires anchorage for its expression

Cited by 20 publications

References 46 publications

Cdc6 Protein Obstructs Apoptosome Assembly and Consequent Cell Death by Forming Stable Complexes with Activated Apaf-1 Molecules

Cdc6 Protein Obstructs Apoptosome Assembly and Consequent Cell Death by Forming Stable Complexes with Activated Apaf-1 Molecules

MAGE-A4 Interacts with the Liver Oncoprotein Gankyrin and Suppresses Its Tumorigenic Activity

Overexpression of Cdk6–cyclin D3 highly sensitizes cells to physical and chemical transformation

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