Phosphorylation of cyclin D1 at Thr 286 during S phase leads to its proteasomal degradation and allows efficient DNA synthesis

Guo, Yang; Ke, Yang; Harwalkar, Jyoti A.; Nye, Jeffrey M; Mason, David R.; Garrett, Michelle D.; Hitomi, Masahiro; Stacey, Dennis W.

doi:10.1038/sj.onc.1208326

Cited by 78 publications

(103 citation statements)

References 27 publications

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“…This technique involves fluorescent staining and accurate quantitation on a cell-by-cell basis, and has been useful in cell cycle studies of cyclin D1 and p27 expression in asynchronous cultures. [24][25][26]33,34 We utilized this single cell based analysis here to critically relate the timing of CDK2 phosphorylation to the initiation of DNA synthesis. First, however, it was necessary to identify an antibody able to recognize CDK2 phosphorylated on Thr-160 in individual cells.…”

Section: Resultsmentioning

confidence: 99%

p27Kip1 and Cyclin Dependent Kinase 2 Regulate Passage Through the Restriction Point

Hitomi¹,

Ke²,

Guo³

et al. 2006

Cell Cycle

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When quiescent cells are stimulated to reenter the cell cycle, growth factors are required only until the restriction point in G 1 phase. After this point the cell no longer requires growth factors, proliferative signaling molecules, or even protein synthesis in order to initiate DNA synthesis, which starts several hours later. Consequently, understanding the molecular nature of the restriction point constitutes one of the major goals in studies of growth regulation. We recently demonstrated that p27Kip1 (p27) regulates passage through G 1 phase in actively proliferating cultures, and initiated these studies to determine if it is also involved in passage through the restriction point following stimulation of quiescent cells. In support of this suggestion, we found that passage through the restriction point requires mitogen-dependent suppression of the high p27 levels normally present in quiescent cells. Moreover, as the culture progresses to mid-G 1 phase, the proportion of cells that pass the restriction point is increased by artificial suppression of p27 levels, while this proportion is reduced by elevation of p27 levels. p27 performs this critical function by regulating the subsequent activating phosphorylation of cyclin dependent kinase (CDK)2, which we also show is necessary for and closely associated with the initiation of DNA synthesis. We conclude that the p27 expression level at mid-G 1 phase determines when a cell passes through the restriction point, and does so by regulating subsequent CDK2 activation.

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Section: Resultsmentioning

confidence: 99%

p27Kip1 and Cyclin Dependent Kinase 2 Regulate Passage Through the Restriction Point

Hitomi¹,

Ke²,

Guo³

et al. 2006

Cell Cycle

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“…What could be the role of this down-regulation in hepatocarcinogenesis? High levels of cyclin D1 in the cell nucleus during the S phase inhibit DNA synthesis; efficient cell proliferation requires glycogen synthase kinase 3hÀdependent phosphorylation of cyclin D1 following its export from the nucleus and subsequent degradation (51). However, the oncogenic alternatively spliced isoform of cyclin D1 lacks the phosphorylation site and remains nuclear (32), showing that at some stage, cancer cells can overcome the inhibition of DNA synthesis by cyclin D1.…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanisms of Liver Carcinogenesis in the Mdr2-Knockout Mice

Katzenellenbogen¹,

Mizrahi²,

Pappo

et al. 2007

Molecular Cancer Research

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Mouse models of hepatocellular carcinoma (HCC) simulate specific subgroups of human HCC. We investigated hepatocarcinogenesis in Mdr2-knockout (Mdr2-KO) mice, a model of inflammationassociated HCC, using gene expression profiling and immunohistochemical analyses. Gene expression profiling showed that although Mdr2-KO mice differ from other published murine HCC models, they share several important deregulated pathways and many coordinately differentially expressed genes with human HCC data sets. Analysis of genome positions of differentially expressed genes in liver tumors revealed a prolonged region of down-regulated genes on murine chromosome 8 in three of the six analyzed tumor samples. This region is syntenic to human chromosomal regions that are frequently deleted in human HCC and harbor multiple tumor suppressor genes. Real-time reverse transcription-PCR analysis of 16 tumor samples confirmed down-regulation of several tumor suppressors in most tumors. We show that in the aged Mdr2-KO mice, cyclin D1 nuclear level is increased in dysplastic hepatocytes that do not form nodules; however, it is decreased in most dysplastic nodules and in liver tumors. We found that this decrease is mostly at the protein, rather than the mRNA, level.These findings raise the question on the role of cyclin D1 at early stages of hepatocarcinogenesis in the Mdr2-KO HCC model. Furthermore, we show that most liver tumors in Mdr2-KO mice were characterized by the absence of B-catenin activation.In conclusion, the Mdr2-KO mouse may serve as a model for B-catenin -negative subgroup of human HCCs characterized by low nuclear cyclin D1 levels in tumor cells and by down-regulation of multiple tumor suppressor genes.

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“…Cyclin D1 induction is a rate-limiting event during cell-cycle entry from quiescence into the G 1 phase (19). For DNA synthesis to occur during S-phase, cyclin D1 proteins should be downregulated (37). Parthenolide treatment at 10 mmol/L concentrations for 3 and 6 hours transiently decreased cyclin D1 protein levels (Fig.…”

Section: Parthenolide Induces S-phase Arrest In Nonpromoted Cells Andmentioning

confidence: 99%

Inhibition of Tumor Promotion by Parthenolide: Epigenetic Modulation of p21

Ghantous

Saikali

Rau

et al. 2012

Cancer Prevention Research

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The promotion stage in the multistep process of epidermal tumorigenesis is NF-kB-dependent, epigenetically regulated, and reversible, thus, a suitable target for chemoprevention. We investigated whether the NF-kB inhibitor, parthenolide, currently in cancer clinical trials, attenuates tumor promotion by modulating the epigenetically regulated NF-kB target genes, p21 and cyclin D1.Parthenolide selectively inhibited the growth of neoplastic keratinocytes while sparing normal ones. Specifically, in JB6Pþ cells, a model of tumor promotion, noncytotoxic parthenolide concentrations abrogated tumor promoter-induced cell proliferation and anchorage-independent growth. Furthermore, parthenolide decreased tumor promoter-induced NF-kB activity, increased p21, and decreased cyclin D1 expression. In parthenolide-treated cells, p21 transcription correlated with relaxed chromatin and p65/NFkB binding at the p21 promoter. However, cyclin D1 transcription correlated more with p65/NF-kB binding than with chromatin structure at the cyclin D1 promoter. Epigenetic regulation by parthenolide seemed specific, as parthenolide did not alter global histone acetylation and methylation and histone deacetylase activity. Because p21 expression by parthenolide was sustained, we used p21-siRNA and p21À/À cancer cells and showed that the loss of p21 is cytoprotective against parthenolide.Low parthenolide concentrations (0.25 mg/kg) inhibited tumor growth of promoted JB6Pþ cells in xenograft immunocompromised mice using two different chemoprevention protocols. Tissue microarray of mouse tumors showed that parthenolide decreased scores of the cell proliferation marker Ki67 and p65/NFkB, whereas it increased p21 expression.These results show that low doses of parthenolide inhibit tumor promotion and epigenetically modulate p21 expression, highlighting the potential role of this drug as a chemopreventive agent and in epigenetic cancer therapy. Cancer Prev Res; 5(11); 1298-309. Ó2012 AACR.

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Phosphorylation of cyclin D1 at Thr 286 during S phase leads to its proteasomal degradation and allows efficient DNA synthesis

Cited by 78 publications

References 27 publications

p27Kip1 and Cyclin Dependent Kinase 2 Regulate Passage Through the Restriction Point

p27Kip1 and Cyclin Dependent Kinase 2 Regulate Passage Through the Restriction Point

Molecular Mechanisms of Liver Carcinogenesis in the Mdr2-Knockout Mice

Inhibition of Tumor Promotion by Parthenolide: Epigenetic Modulation of p21

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