Concurrent amplification of cyclin E and CDK2 genes in colorectal carcinomas

Kono, Kenji; Yasui, Wataru; Kuniyasu, Hiroki; Yokozaki, Hiroshi; Akama, Yoshihiko; Yunotani, Seiji; Hisatsugu, Takeharu; Tahara, Eiichi

doi:10.1002/ijc.2910620107

Cited by 109 publications

(80 citation statements)

References 12 publications

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“…Cyclin E/Ha-ras transformed cells ful®l the classical criteria for malignant cells as they are able to grow and form colonies independent of a solid support and give rise to malignant tumours in syngeneic animals. This oncogenic activity of cyclin E is most interesting in the light of recent reports that implicate the deregulation of cyclin E in human cancer particularly breast carcinoma (Keyomarsi et al, 1995;Kitahara et al, 1995) and strongly suggest a direct role of aberrant cyclin E expression in the formation of a number of human malignancies that bear ampli®ed cyclin E genes. With this activity of cyclin E and recent ®ndings that ascribe a similar oncogenic potential to CDK4 (Haas et al, 1997) and CDC25 (Galaktionov et al, 1995) as well as the similar already known activity of D-type cyclins strongly suggest that all genes encoding positive G1 cell cycle regulators are in general protooncogenes and that their deregulated expression leads to a loss of growth control that is incremental in the process of malignant transformation.…”

Section: Discussionmentioning

confidence: 82%

Malignant transformation by cyclin E and Ha-Ras correlates with lower sensitivity towards induction of cell death but requires functional Myc and CDK4

Haas

Johannes²,

Geisen

et al. 1997

Oncogene

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We demonstrate in this paper that the G1 phase speci®c cell cycle regulator cyclin E is able to provoke focus formation when cotransfected with activated Ha-ras into primary rat embryo ®broblasts (REFs). Cyclin E/Ha-ras transformed cells are highly tumorigenic in synergeneic rats, are able to form colonies in soft agar and show protection towards apoptosis upon serum starvation or DNA damage compared to cells transformed by the combination of Myc, cyclin D1 or SV40 large T-antigen and Ha-ras. Lines that were established after cyclin E/ Ha-ras or cyclin D1/Ha-ras transformation contain a large percentage of polyploid cells. This was not observed in cells transformed with other oncoproteins and Ha-ras pointing to an involvement of D-and E type cyclins in genomic instability. The cyclin dependent kinase inhibitors p21 and p27 but also p16 completely abrogate focus formation by cyclin E and Ha-ras suggesting that the oncogenic activity of cyclin E still requires functional G1 speci®c cyclin/CDK complexes. Moreover, inhibition of Myc function also blocks the oncogenic activity of cyclin E indicating a requirement of Myc for cyclin E function. The ®ndings presented here demonstrate that cyclin E can act as an oncoprotein with a potential involvement in genomic instability and the prevention of cell death. Our data also present more evidence for a strict functional interdependency between G1 cyclin/CDK complexes and c-Myc.

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Section: Discussionmentioning

confidence: 82%

Malignant transformation by cyclin E and Ha-Ras correlates with lower sensitivity towards induction of cell death but requires functional Myc and CDK4

Haas

Johannes²,

Geisen

et al. 1997

Oncogene

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“…43 Although amplification and overexpression of cyclin E have been shown in several human solid tumors, 43,44 little is known about the involvement of cyclin E in HCC. In the present study, we found increased levels of cyclin E protein and its kinase activity in moderately and poorly differentiated HCC (Fig.…”

Section: Discussionmentioning

confidence: 99%

Cyclins and cyclin-dependent kinases: Comparative study of hepatocellular carcinoma versus cirrhosis

et al. 2003

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Increasing evidence has indicated that perturbation of cyclins is one of the major factors leading to cancer. The aim of this study was not only to investigate various cell cycle-related kinase activities in hepatocellular carcinoma (HCC), but also to analyze the difference of cell cycle-related kinase activity levels between hepatitis C virus (HCV)-induced HCC and HCVinduced cirrhosis. The protein levels of cyclins D1, E, A, and H, and of cyclin dependent kinase 1 (Cdk1), Cdk2, Cdk4, Cdk6, and Cdk7 in HCC and in surrounding nontumorous cirrhosis were determined by Western blot. The enzymatic activities of cyclins D1, E, A, Cdk1, Cdk4, Cdk6, Cdk7, and Wee1 were measured using in vitro kinase assays. Protein levels and kinase activities of cyclin D1, Cdk4, cyclin E, cyclin A, and Wee1 were significantly elevated in HCC compared with surrounding cirrhotic tissues. The enhanced cyclin D1-related kinase activity in HCC was accompanied by the up-regulation of Cdk4 activity, but not Cdk6 activity. The kinase activities of Cdk6, Cdk7, and Cdk1 did not differ between HCC and surrounding cirrhotic tissues. In addition, the protein levels and kinase activities of cyclin D1, Cdk4, and cyclin E were higher in poorly differentiated HCC and advanced HCC. In conclusion, the increases of cyclin D1, Cdk4, cyclin E, cyclin A, and Wee1 play an important role in the development of HCC from cirrhosis. Cyclin D1, Cdk4, and cyclin E activation may be closely related to the histopathologic grade and progression of HCC. R ecent studies, including our research, have revealed that the deranged expression of cell cyclerelated proteins is one of the major factors contributing to hepatocellular carcinoma (HCC) development. 1-6 Here we investigated biochemical differences of various cell cycle-related kinase activities and protein levels in cirrhosis and HCC.Specific cyclin/cyclin-dependent kinase (Cdk) complexes are activated at different intervals during the cell cycle. 7-15 Cyclin D1/Cdk4 and cyclin D1/Cdk6 are activated in mid-G1 (Fig. 1, phase 1), whereas cyclin E/Cdk2 complexes are required for the G1/S transition (Fig. 1, phase 2), cyclin A/Cdk2 for the progression of DNA synthesis (Fig. 1, phase 3), and cyclin A-B/Cdk1 for the G2/M transition (Fig. 1, phase 4) of mitosis. The activation of cyclin D1/Cdk4 and cyclin D1/Cdk6 complexes at mid-G1 is responsible for the phosphorylation of retinoblastoma protein (pRb), and 2 Rb related proteins, p107, and p130. Members of the pRb family form complexes with transcription factors of the E2F family. 16 This interaction with pRb family members blocks the transcriptional activity of E2Fs; the complexes formed also function as active transcriptional repressor complexes at the promoters of some cell cycle genes. Phosphorylation of the pRb family inhibits the interaction with E2F family transcription factor and permits the expression of genes necessary for S-phase entry (cyclin A, proliferating cell nuclear antigen, and so on). 17 The expression of cyclins E and A at mid-to late-G1 permits the form...

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“…26 It is also well known that dysregulation of serine/threonine kinases may lead to uncontrolled cell proliferation and hence to cancer. For example, amplification of serine/threonine kinase genes such as CDK2 at 12q13, CDK4 at 12q14, PS6K at 17q23, and STK15 at 20q13 were observed in tumors of the ovary, 27 breast, 28,29 colon, 30 brain, 31,32 and cervix. 33 The strong association of TRIO amplification with high grade, advanced stage, and tumor cell proliferation suggests TRIO as appropriate oncogene candidate when amplified and overexpressed in bladder tumors.…”

Section: Discussionmentioning

confidence: 99%

TRIO Amplification and Abundant mRNA Expression Is Associated with Invasive Tumor Growth and Rapid Tumor Cell Proliferation in Urinary Bladder Cancer

Zheng

Simon

Mirlacher

et al. 2004

The American Journal of Pathology

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Studies by comparative genome hybridization have suggested that 5p amplification is related to tumor progression in urinary bladder cancer. In this study seven genes (TAS2R, ADCY2, DNAH5, CTNND2, TRIO, ANKH, and MYO10) located to 5p15.31-5p15.1 were analyzed by fluorescence in situ hybridization using a tissue microarray containing samples from tumors and cell lines with known 5p amplification by comparative genome hybridization. Amplification frequency was highest for TRIO, which maps to 5p15.2 and encodes a protein with a putative role in cellcycle regulation. To further investigate the role of TRIO amplification in bladder cancer, a tissue microarray containing samples from 2317 bladder tumors was used for fluorescence in situ hybridization analysis. TRIO amplification was strongly associated with invasive tumor phenotype, high tumor grade, and rapid tumor cell proliferation (Ki67 LI) (P < 0.0001 each). Only 7 of 456 pTaG1/G2 tumors (1.5%) but 62 of 485 pT1-4 carcinomas (12.8%) had TRIO amplification. TRIO amplification was not associated with poor prognosis. Using a frozen bladder tumor tissue microarray RNA in situ hybridization confirmed that TRIO is up-regulated in amplified tumors. It is concluded that TRIO up-regulation through amplification has a potential role in bladder cancer progression. Studies by comparative genomic hybridization (CGH) demonstrated gains and amplifications at many different chromosomal loci mainly in invasive bladder cancer. 1 Gene copy number increase is an important mechanism leading to abnormal expression of known oncogenes such as MYC at 8q24, CCND1 at 11q13, or HER2 at 17q21. 2-4 However, most of the chromosomal regions found amplified in bladder cancer 1 do not contain known oncogenes, suggesting that many amplification target genes remain to be identified.Amplifications of the short arm of chromosome 5 are of particular interest. In previous CGH studies 5p amplification was found to be one of the few alterations occurring more frequently in muscle invasive tumors (stage pT2 and higher) than in early invasive cancers (stage pT1). 5 Our hypothesis of a role of 5p amplification for bladder cancer progression was further corroborated by the results of a second CGH study finding a significant association between 5p amplifications and an increased risk for tumor progression in a series of pT1 carcinomas. 6 Because amplifications often cover large areas of 5p in bladder cancer, it is difficult to narrow down the region of amplification using positional cloning approaches. Based on our CGH studies, one of the most common sites of amplification is in the 5p15-p14 region. 5 In an attempt to find oncogene candidates among known genes allocated in this chromosomal area, we became interested in TRIO located at 5p15.2. 7 The TRIO protein contains a serine/threonine kinase domain and two guanine nucleotide exchange factor domains for the family of Rho-like GTPases, specific for Rac1 and RhoA. 8 These functional domains suggest that this enzyme may play a role in signaling pathways contro...

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Concurrent amplification of cyclin E and CDK2 genes in colorectal carcinomas

Cited by 109 publications

References 12 publications

Malignant transformation by cyclin E and Ha-Ras correlates with lower sensitivity towards induction of cell death but requires functional Myc and CDK4

Malignant transformation by cyclin E and Ha-Ras correlates with lower sensitivity towards induction of cell death but requires functional Myc and CDK4

Cyclins and cyclin-dependent kinases: Comparative study of hepatocellular carcinoma versus cirrhosis

TRIO Amplification and Abundant mRNA Expression Is Associated with Invasive Tumor Growth and Rapid Tumor Cell Proliferation in Urinary Bladder Cancer

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