Overexpression of cyclin E protein is closely related to the mutator phenotype of colorectal carcinoma

Sutter, Thomas R.; Dansranjavin, Temuujin; Lubiński, Jan; Dębniak, Tadeusz; Giannakudis, Joannis; Hoang‐Vu, Cuong; Dralle, Henning

doi:10.1007/s00384-002-0390-y

Cited by 22 publications

(20 citation statements)

References 30 publications

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“…20 One thing to be noted is that cyclin E protein is accumulated in the tumor cells in a considerable proportion of colorectal cancers. 21 On the basis of these observations, in the present study, we evaluated the regulation of Parkin gene expression in association with cell cycle regulation in colonic epithelial cells. …”

mentioning

confidence: 99%

Attenuation of proteolysis‐mediated cyclin E regulation by alternatively spliced Parkin in human colorectal cancers

Ikeuchi

Marusawa

Fujiwara

et al. 2009

Intl Journal of Cancer

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Parkin has a critical role in the ubiquitin-proteasome system as an E3-ligase targeting several substrates. Our recent finding that Parkin-deficient mice are susceptible to tumorigenesis provided evidence that Parkin is a tumor suppressor gene. Dysfunction of the Parkin gene is frequently observed in various human cancers, but the mechanism underlying the cell cycle disruption induced by Parkin dysfunction that leads to carcinogenesis is not known. Here, we demonstrated that Parkin expression in colonic epithelial cells is regulated in a cell cycle-associated manner. Epidermal growth factor (EGF) stimulation upregulated Parkin gene expression in human colon cells. Inhibition of the phosphoinositide 3-kinase [PI(3)K]-Akt-dependent pathways suppressed growth factorinduced Parkin expression. The expression of alternatively spliced Parkin isoforms with various deletions spanning exons 3-6 was detected in 18 of 43 (42%) human colorectal cancer tissues. Wildtype Parkin induced the degradation of cyclin E protein, but the alternatively spliced Parkin identified in colon cancers showed defective proteolysis of cyclin E. These findings indicate that Parkin expression is induced by growth factor stimulation and is involved in the cell cycle regulation of colon cells. Tumor-specific expression of alternatively spliced Parkin isoforms might contribute to enhanced cell proliferation through the attenuation of proteolysismediated cyclin E regulation in human colorectal cancers. ' UICCKey words: Parkin; colorectal cancer; cyclin E; cell cycle; EGF Parkin functions in the ubiquitin-proteasome system as an E3 ligase, facilitating the ubiquitination of target proteins. [1][2][3] Parkin is developmentally regulated with induced expression during cell differentiation, and little to no expression in immature cells. 4 Several putative candidate substrates of Parkin-mediated proteolysis have been identified, including a-synphilin, a-synuclein interacting protein, synphilin-1 and Pael-R. 5,6 Recently, it was revealed that deficiency of Parkin potentiates the accumulation of cyclin E protein in cultured postmitotic neurons exposed to the glutamatergic excitotoxin kainate, suggesting that the cell cycle regulator, cyclin E, is a putative substrate of the Parkin ubiquitin ligase complex in neurons. 7 Since Parkin was first identified as a gene implicated in autosomal recessive juvenile Parkinsonism, one form of familial Parkinson disease, 8 attention has been focused on unveiling the role of Parkin in neurons. The expression and regulation of Parkin in epithelial cells as well as the role of Parkin in cell cycle regulation, however, has not been clarified.A loss of heterozygosity within chromosomal region 6q25-q27 containing the Parkin gene is frequently observed in various human tumors, including ovarian, 9-11 breast, 12 renal 13 and lung cancers. 14,15 In addition, the Parkin gene is frequently deleted in breast, ovarian and liver cancers. [16][17][18] We recently demonstrated that Parkin-deficient mice lacking exon 3 of the Parkin ge...

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confidence: 99%

Attenuation of proteolysis‐mediated cyclin E regulation by alternatively spliced Parkin in human colorectal cancers

Ikeuchi

Marusawa

Fujiwara

et al. 2009

Intl Journal of Cancer

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“…For example, cyclin D1, cyclin E and cdk4 have been shown to be overexpressed in some human colon cancers, and p27 has been shown to be underexpressed or abnormally localized in other cancers, yet the role of TGF-b receptor inactivation in the altered expression of these proteins in primary colon cancer is not known. [35][36][37][38] Previous studies in the Apc Min/1 mouse model have shown concurrent loss of TGFBR2 expression and increased expression of cyclin D1 and cdk4 in intestinal tumors implicating impaired TGF-b signaling in the increased expression of these proteins. 27 Consequently, we investigated whether MSI-mediated TGFBR2 mutations in the BAT-RII mutation hot spot are associated with alterations in cell proliferation and cell cycle-associated protein expression in primary human MSI colon cancers.…”

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confidence: 99%

Proliferation and Cdk4 expression in microsatellite unstable colon cancers with TGFBR2 mutations

Grady

Willis

Trobridge

et al. 2005

Intl Journal of Cancer

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Approximately 15% of human colon cancers have microsatellite instability (MSI) and carry frameshift mutations in a polyadenine tract (BAT-RII) in the type II transforming growth factor b (TGFb) receptor (TGFBR2), a required component of the TGF-b receptor. The BAT-RII mutations in MSI colon cancers make the tumors resistant to the effects of TGF-b. In cultured epithelial cells, TGF-b can inhibit cell proliferation and induce apoptosis, and in vitro it can regulate the expression of a variety of cyclins, cyclin-dependent kinases (cdks) and cdk inhibitors. These effects are context-and tissue type-dependent, raising questions about which of these in vitro effects of TGF-b signaling inactivation contribute to the formation of primary colon cancer. Thus, this study sought to determine the pathogenetically relevant effects of TGFBR2 inactivation in primary MSI colon cancers with mutant BAT-RII. Colon cancers with mutant BAT-RII were found to have increased proliferation compared to cancers with wild-type BAT-RII. Assessment of cdk4, cyclin D1 and p27 kip1 expression revealed that only cdk4 expression was increased in the cancers with mutant BAT-RII. In order to determine if TGFBR2 inactivation was the cause of these changes, TGFBR2 was reconstituted in an MSI colon cancer cell line, resulting in decreased proliferation and decreased cdk4 expression and kinase activity. These results suggest that TGFBR2 mutations in primary colon cancers may be responsible for the increased proliferation and cdk4 expression in these tumors and provide evidence that deregulation of cdk4 is a pathogenic in vivo consequence of TGFBR2 inactivation in primary colon cancer. ' 2005 Wiley-Liss, Inc.Key words: colon cancer; TGF-b; cdk4; proliferation TGF-b is a potent negative regulator of epithelial cell growth and in cell culture can cause complete growth inhibition and induce apoptosis of nontransformed colon epithelial cells. 1,2 TGFb mediates its effects through a heteromeric cell surface receptor that consists of 2 serine-threonine kinases, the type I and type II TGF-b receptors. During the malignant transformation of colon epithelial cells, the acquisition of resistance to TGF-b-mediated growth inhibition occurs commonly, suggesting it has a significant pathogenic role in the formation of colon cancer. 2-4 Indeed, previous studies have shown that the malignant progression of colon adenoma cell lines directly correlates with the acquisition of TGFb resistance in the cultured cells. 2,4 Mechanisms of the TGF-b resistance described in colon cancers include mutations in the type II TGF-b receptor (TGFBR2) 5-7 as well as mutations in the TGFb signal transduction molecules MADH2/SMAD2 and MADH4/ SMAD4. [8][9][10] The first of these mutations to be described were TGFBR2 frameshift mutations clustered within a microsatellitelike 10 base pair polyadenine repeat within the TGFBR2 coding region (the BAT-RII tract). Such BAT-RII frameshift mutations are characteristic of colon cancers that arise in the setting of microsatellite instability (MSI), a...

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“…The deregulation of cyclin E expression in colorectal cancer cells was reported to be involved in both CIN and MIN tumor phenotypes. 5,7 Recently, the characterization of cyclin E LMW forms in breast tumors shed new light on cyclin E's role in cell transformation and cancer progression, 17 and prompted us to investigate the presence of LMW forms in colon cancer cells by employing an antibody specifically recognizing cyclin E C-terminus, the common region present in all six isoforms (EL1-6).…”

Section: Resultsmentioning

confidence: 99%

“…5,6 The critical role of cyclin E in colorectal cancer cells is confirmed by the fact that it appears to be deregulated also in a significant percentage of MIN tumors. 7 Moreover, increasing protein levels of cyclin E are considered a marker for the transition from adenoma to adenocarcinoma, the key step in colorectal cancerogenesis. 8 Several mechanisms could explain the high levels of cyclin E in colorectal cancer cells, some increasing the transcription rate, such as gene amplification 9 and up-regulation of E2F transcription factors, 10 others decreasing the degradation of the protein, as for inactivating mutation of hCDC4.…”

Section: Introductionmentioning

confidence: 99%

Tumor-specific hyperactive low-molecular-weight cyclin E isoform detection and characterization in non-metastatic colorectal tumors

Corin¹,

Giacomo²,

Lastella³

et al. 2006

Cancer Biology & Therapy

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Purpose: Several molecules involved in cancer biology have been studied as potential prognostic markers. Recently, overexpression of cyclin E and its low-molecular-weight (LMW) isoforms has been reported to be the most prominent prognostic marker in breast cancer, surpassing proliferation index, ploidy, and axillary nodal involvement. Furthermore, cyclin E and p53 are considered the main factors controlling the euploid equilibrium in human cells. We investigated the status of cyclin E and p53 in cell lines and tissue samples of colorectal cancer, one of the leading causes of death from a tumor in the Western world.Experimental design: We analyzed colorectal cancer cells, from established cell lines and patient specimens, to determine the protein levels of cyclin E and p53, and to detect p53 and APC mutations, microsatellite and chromosome instability. In addition, we assessed the presence of cyclin E LMW isoforms and their enzymatic activity.Results: Colorectal cancer cells expressed hyperactive LMW forms both in vitro and in vivo. These tumor-specific isoforms are correlated to genomic instability even in p53-proficient cells, and represented a constant feature in the tumors analyzed.Conclusions: In colorectal cancer, the formation of cyclin E LMW forms is an early event leading to DNA-damage checkpoint-independent proliferation. Collectively, our results provide evidence that evaluation of LMW forms could represent a novel tool in the molecular characterization of colorectal tumors aimed at identifying sensitive prognostic factors and uncovering subsets of high-risk patients within the traditional categories.

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Overexpression of cyclin E protein is closely related to the mutator phenotype of colorectal carcinoma

Cited by 22 publications

References 30 publications

Attenuation of proteolysis‐mediated cyclin E regulation by alternatively spliced Parkin in human colorectal cancers

Attenuation of proteolysis‐mediated cyclin E regulation by alternatively spliced Parkin in human colorectal cancers

Proliferation and Cdk4 expression in microsatellite unstable colon cancers with TGFBR2 mutations

Tumor-specific hyperactive low-molecular-weight cyclin E isoform detection and characterization in non-metastatic colorectal tumors

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