Cell cycle regulation of the cyclin A, cdc25C and cdc2 genes is based on a common mechanism of transcriptional repression.

Zwicker, Jörk; Lucibello, Frances C.; Wolfraim, Lawrence A.; Groß, Claudia; Truss, Mathias; Engeland, Kurt; Müller, Rolf

doi:10.1002/j.1460-2075.1995.tb00130.x

Cited by 298 publications

(354 citation statements)

References 37 publications

(59 reference statements)

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“…The increase in the normally cycling cells is presumably due to an e ect on the G 1 fraction (*60% of the cell population) where CDF-1 is active. Only a marginal e ect of SV-LT was seen with a reporter plasmid containing a mutated CDE (Lucibello et al, 1995;Zwicker et al, 1995b) (data not shown), indicating that CDF-1 is an essential target in the deregulation of the cdc25C promoter by the viral oncoprotein.…”

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confidence: 93%

“…The proto-type of this group of genes is cdc25C (Lucibello et al, 1995), which is controlled by a novel repressor, termed CDF-1 (Liu et al, 1997). CDF-1 binds cooperatively to two contiguous elements, the CDE and CHR (Zwicker et al, 1995b) and seems to be unrelated to all known E2F and DP family members (Liu et al, 1997). CDF-1 is also the major regulator of the cyclin A gene (Zwicker et al, 1995b).…”

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confidence: 99%

“…CDF-1 binds cooperatively to two contiguous elements, the CDE and CHR (Zwicker et al, 1995b) and seems to be unrelated to all known E2F and DP family members (Liu et al, 1997). CDF-1 is also the major regulator of the cyclin A gene (Zwicker et al, 1995b). As shown by in vivo footprinting, occupation of the CDE and CHR elements is inversely correlated with promoter activity during the cell cycle, and mutations in either element lead to constitutive transcription (Lucibello et al, 1995;Zwicker et al, 1995b).…”

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confidence: 99%

“…CDF-1 is also the major regulator of the cyclin A gene (Zwicker et al, 1995b). As shown by in vivo footprinting, occupation of the CDE and CHR elements is inversely correlated with promoter activity during the cell cycle, and mutations in either element lead to constitutive transcription (Lucibello et al, 1995;Zwicker et al, 1995b). It is however unclear what the e ect of viral oncoproteins on CDF-1 mediated repression is.…”

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The SV40 large T oncoprotein disrupts DNA-binding of the cell cycle-regulated transcriptional repressor CDF

1999

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A hallmark of neoplastic transformation by DNA tumor viruses is the deregulation of cell cycle genes. At least in some genes, this deregulation appears to be due to the oncoprotein-mediated disruption of complexes between E2F and pocket proteins and the ensuing generation of transcriptionally active free E2F. In the present study, we have analysed the e ect of the SV40 large T oncoprotein (SV-LT) on the function of a di erent cell cycle-regulated transcriptional repressor, CDF, which is the principal regulator of the cdc25C, cyclin A and cdc2 genes. As shown by genomic footprinting of sorted G 1 and G 2 cell populations, transformation by SV-LT completely abrogated protection of the CDF binding site (CDE-CHR) in the cdc25C promoter. In agreement with this observation, expression of the SV-LT in ®broblasts led to a dramatic up-regulation of the cdc25C promoter in cells synchronized in G 0 . These ®ndings indicate that the oncoprotein-mediated dissociation of the CDF repressor protein from its cognate DNA-binding site is a major mechanism in virus-induced transcriptional deregulation.

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The SV40 large T oncoprotein disrupts DNA-binding of the cell cycle-regulated transcriptional repressor CDF

1999

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“…The hypophosphorylated form of these proteins binds the transcription factor E2F, and upon phosphorylation, E2F is released and can activate transcription of S phase-speci®c genes (Draetta, 1994;Lam and La Thangue, 1994;Mittnacht, 1998). Among the genes containing E2F-binding sites in their promoter regions there are those coding for enzymes and proteins that are essential for DNA replication such as DNA polymerase a, thymidin kinase, ribonucleotide reductase, cyclin A and cyclin E (Botz et al, 1996;Dalton, 1992;Dou et al, 1994;Geng et al, 1996;Zwicker et al, 1995). The activation of cyclin D/cdk4 and phosphorylation of pRb is thus a limiting step for G1 progression.…”

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[Lys61]N-Ras is able to induce full activation and nuclear accumulation of Cdk4 in NIH3T3 cells

et al. 2000

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The elements of the cell cycle regulatory machinery activated by the oncogenic form of Ras, [Lys 61 ]N-Ras, have been analysed in NIH3T3 cells. We demonstrate that [Lys 61 ]N-Ras expression is able to induce full cdk4 activation. As already reported, oncogenic Ras expression was su cient to induce cyclin D1 and p21 cip1 expression and their association with cdk4. Furthermore, serum-starved [Lys 61 ]N-Ras NIH3T3 cells showed nuclear accumulation of cyclin D1 and cdk4 not observed in serum-starved NIH3T3 cells. This accumulation of cdk4 into the cell nucleus observed in serum-starved [Lys 61 ]NRas NIH3T3 cells was inhibited by a microinjection of neutralizing anti-Ras antibodies. Thus, active [Lys 61 ]NRas was a su cient signal to induce nuclear accumulation of cyclin D1/cdk4, leading to its full activation. Transfection of [Lys 61 ]N-Ras NIH3T3 cells with an inactive form of MEK or their treatment with PD 98059, showed that nuclear translocation of cdk4 was MEK dependent. Interestingly, cells constitutively expressing [Lys 61 ]N-Ras did not inactivate pRb and did not proliferate in the absence of serum. This may be due to the fact that although association of cdk2 with cyclin E and the translocation of those complexes to the nucleus were achieved, [Lys 61 ]N-Ras expression was not su cient to induce cdk2 activation. The high levels of p27 kip1 that were found in cyclin E/cdk2 complexes may be responsible for the inability of oncogenic Ras to activate this kinase. In consequence, oncogenic alterations that lead to a decrease in p27 kip1 bound to cyclin E may cooperate with Ras to induce full cdk2 activation, pRb inactivation and thus cell proliferation. Oncogene (2000) 19, 690 ± 699.

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Prognostic significance of cyclin A in gastric cancer

Mrena

Wiksten

Kokkola

et al. 2006

Intl Journal of Cancer

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High level of cyclin A promotes carcinogenesis, and overexpression of cyclin A has been associated with poor prognosis of cancer patients. We validated the prognostic role of cyclin A in gastric cancer and evaluated its correlation with expression of an mRNA stability factor HuR. From 342 consecutive histologically confirmed gastric cancer patients were obtained 325 representative tissue specimens for cyclin A and 316 for HuR immunohistochemistry. Specimens were stained by cyclin A and HuR specific monoclonal antibodies. Nuclear immunostaining detected in 5% of the tumor cells was considered the cut-off for cyclin A positivity. Positive HuR immunoreactivity was scored as nuclear or cytoplasmic. Associations between scores, clinicopathological factors and survival were calculated by the v 2 -test, Fisher's exact test, Kaplan-Meier test and Cox model. Cyclin A detected in the nuclei of cancer cells was positive in 55% (179 of 325) of the specimens; 40% (127 of 316) of the specimens had cytoplasmic and 88% (279 of 316) nuclear immunoreactivity of HuR. Cyclin A expression was an independent prognostic factor for poor survival. Cyclin A immunoreactivity was associated with old age, high stage, proximal location of the tumor, intestinal type, noncurative resection, advanced penetration depth and with nodal metastases but not distant metastases. Furthermore, cyclin A expression was associated with cytoplasmic HuR expression, whereas no association with nuclear HuR was evident. Cyclin A is an independent prognostic factor in gastric cancer, and one mechanism for its overexpression may depend on cytoplasmic localization of HuR. ' 2006 Wiley-Liss, Inc.Key words: cyclin A; HuR; gastric cancer; prognosis; survival Cyclin A belongs to the cyclin protein superfamily, and it can activate two different cyclin-dependent kinases, CDK1 and CDK2. The level of cyclin A accumulates progressively throughout the interphase and disappears rapidly at the end of mitosis. Currently, phosphorylated cyclin A-CDK complex is suggested to play an important role in the initiation of DNA replication in the S phase. The precise function of cyclin A in mitosis is unclear, but it may prevent other cyclins from degradation. Overexpression of cyclin A and dysregulation of CDK-cyclin complexes promote tumor cell growth, which can be facilitated by phosphorylation of oncoproteins and tumor suppressors. 1,2 In gastric cancer, cell-cycle regulators have been connected with poor prognosis. For example, overexpression of cyclin E, which also binds to CDK2 and controls the G1-S transition, has been associated with aggressive disease. 3,4 Furthermore, strongly positive cyclin E in the tumors of patients having surgery with intent to cure is a marker of poor prognosis, and concurrent expression of cyclin E and p53 is an independent prognostic factor. 5 However, there are also reports indicating that cyclin E expression does not correlate with clinicopathological parameters, 6 or is associated with good prognosis. 7 Overexpression of cyclin A correlates with po...

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Cell cycle regulation of the cyclin A, cdc25C and cdc2 genes is based on a common mechanism of transcriptional repression.

Cited by 298 publications

References 37 publications

The SV40 large T oncoprotein disrupts DNA-binding of the cell cycle-regulated transcriptional repressor CDF

The SV40 large T oncoprotein disrupts DNA-binding of the cell cycle-regulated transcriptional repressor CDF

[Lys61]N-Ras is able to induce full activation and nuclear accumulation of Cdk4 in NIH3T3 cells

Prognostic significance of cyclin A in gastric cancer

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