Ectopic expression of cyclin E allows non-endomitotic megakaryoblastic K562 cells to establish re-replication cycles

García, Paloma; Frampton, Jonathan; Ballester, Alicia; Calés, Carmela

doi:10.1038/sj.onc.1203494

Cited by 32 publications

(52 citation statements)

References 58 publications

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“…Furthermore, the adenoviruses used in this study contained a strong constitutive promoter which resulted in sustained expression of cyclin E and activation of cyclin E/cdk2. The appearance of polyploid hepatocytes is consistent with recent studies in cell culture systems showing that sustained cyclin Eassociated kinase activation leads to the accumulation of polyploid nuclei (Garcia et al, 2000).…”

Section: In Vivo Studiessupporting

confidence: 78%

Induction of hepatocyte proliferation and liver hyperplasia by the targeted expression of cyclin E and skp2

et al. 2001

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Cells in culture become competent to replicate in the absence of growth factor after progressing beyond the late G1 restriction point, suggesting that a set of genes expressed during G1 phase is su cient to trigger completion of the cell cycle. However, this has not been demonstrated in an in vivo system. In this study, we examined whether transfection of genes associated with the G1/S transition could trigger hepatocyte replication. Co-transfection of cyclin E and skp2 synergistically promoted cell cycle progression in cultured primary hepatocytes in the absence of mitogen or in the presence of growth inhibitors. Furthermore, transfection of hepatocytes in vivo with cyclin E and skp2 promoted abundant hepatocyte replication and hyperplasia of the liver. These studies con®rm that transfection with a small number of genes can trigger proliferation of quiescent hepatocytes in vivo, and suggest that therapies to enhance liver regeneration by targeting cell cycle control genes may be feasible. Oncogene (2001) 20, 1825 ± 1831.

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Section: In Vivo Studiessupporting

confidence: 78%

Induction of hepatocyte proliferation and liver hyperplasia by the targeted expression of cyclin E and skp2

et al. 2001

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“…Whether the former or the latter underlies the aberrant morphology and biology of Hodgkin and Reed-Sternberg cells is an important unresolved issue. Expression of cyclin E is required for endoreduplication in trophoblasts 29 as well as in megakaryocytes 30 and overexpression of cyclin E has been correlated with polyploidy and chromosome instability in human tumors (Hubalek et al 31 and references therein). Whether and how overexpression of cyclin A might contribute to the cell cycle abnormalities observed in Hodgkin and ReedSternberg cells is not clear at the moment.…”

Section: Discussionmentioning

confidence: 99%

Aberrant expression of cell cycle regulators in Hodgkin and Reed–Sternberg cells of classical Hodgkin's lymphoma

et al. 2005

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The characteristic Hodgkin and Reed-Sternberg cells of classical Hodgkin's lymphoma, although highly positive for proliferation markers, do not accumulate to excessive cell numbers. These cells are characterized by abortive mitotic cycles, leading to multinucleation or cell death in mitosis. We have previously described high expression of G 1 -phase cyclins in classical Hodgkin's lymphoma, which could explain the high percentage of cells staining for proliferation markers. To further our understanding of proliferation control in classical Hodgkin's lymphoma, we extended our immunohistochemical analysis to the main S-phase cyclin, cyclin A, and its regulators p21 CIP1 and p27 KIP1 . Expression of proliferating cell nuclear antigen (PCNA) was used as an additional marker for cells being in either S-or G 2 -phase. In 47% (112/239) of classical Hodgkin's lymphoma cases p21 CIP1 was detected within a mean frequency of 15% positive Hodgkin's and Reed-Sternberg cells per case. Similarly, 47% (116/249) of the cases stained positively for p27 KIP1 with a mean frequency of expression in Hodgkin's and Reed-Sternberg cells of 12%. In contrast, 90% of the cells in all 246 evaluable classical Hodgkin's lymphoma cases were positive for PCNA. In addition, 98% of Hodgkin's and Reed-Sternberg cells in 99% (250/253) of the cases stained strongly positive for cyclin A. These findings further corroborate the hypothesis that Hodgkin and Reed-Sternberg cells exhibit a disturbed cell cycle with an abnormally short or even absent G 1 -phase. In contrast to other tumors, expression of PCNA or cyclin A had no prognostic value for patient survival.

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“…Cell-surface immunofluorescent staining was performed by incubating cells with antibodies against glycoprotein IIIa/CD61 or glycophorin A conjugated to FITC (Becton Dickinson) as previously described (11). DNA content was determined by staining with 50 g/ml propidium iodide.…”

Section: Methodsmentioning

confidence: 99%

“…Expression vector pcDNA3-ESG was generated by subcloning an XbaI fragment containing the ESG open reading frame into the pcDNA3 polycloning site (Invitrogen). The construction of the cycA(Ϫ875)luc reporter plasmid containing the human cyclin A promoter has been described elsewhere (11).…”

Section: Methodsmentioning

confidence: 99%

“…In vitro and in vivo experimental approaches have shown that both G 1 /S and G 2 /M cell cycle transitions have to be regulated for megakaryocytes to achieve polyploidization (4 -12). Specifically, both cyclin D3-Cdk2 and cyclin E-Cdk2 complexes have been proposed as the most likely candidates to drive megakaryocytic polyploidization (4,11,12). However, little is known about the mechanisms upstream of the cell cycle machinery that ultimately control the proper establishment of endomitotic cycles in differentiating megakaryoblasts.…”

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confidence: 99%

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Heterologous Expression of the Transcriptional Regulator Escargot Inhibits Megakaryocytic Endomitosis

Ballester¹,

Frampton²,

Vilaboa³

et al. 2001

Journal of Biological Chemistry

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Certain cell types escape the strict mechanisms imposed on the majority of somatic cells to ensure the faithful inheritance of parental DNA content. This is the case in many embryonic tissues and certain adult cells such as mammalian hepatocytes and megakaryocytes. Megakaryocytic endomitosis is characterized by repeated S phases followed by abortive mitoses, resulting in mononucleated polyploid cells. Several cell cycle regulators have been proposed to play an active role in megakaryocytic polyploidization; however, little is known about upstream factors that could control endomitosis. Here we show that ectopic expression of the transcriptional repressor escargot interferes with the establishment of megakaryocytic endomitosis. Phorbol ester-induced polyploidization was inhibited in stably transfected megakaryoblastic HEL cells constitutively expressing escargot. Analysis of the expression and activity of different cell cycle factors revealed that Escargot affects the G 1 /S transition by influencing Cdk2 activity and cyclin A transcription. Nuclear proteins that specifically bind the Escargot-binding element were detected in endomitotic and non-endomitotic megakaryoblastic cells, but down-regulation occurred only during differentiation of cells that become polyploid. As Escargot was originally implicated in ploidy maintenance of Drosophila embryonic and larval cells, our results suggest that polyploidization in megakaryocytes might respond to mechanisms conserved from early development to adult cells that need to escape normal control of the diploid state.

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Ectopic expression of cyclin E allows non-endomitotic megakaryoblastic K562 cells to establish re-replication cycles

Cited by 32 publications

References 58 publications

Induction of hepatocyte proliferation and liver hyperplasia by the targeted expression of cyclin E and skp2

Induction of hepatocyte proliferation and liver hyperplasia by the targeted expression of cyclin E and skp2

Aberrant expression of cell cycle regulators in Hodgkin and Reed–Sternberg cells of classical Hodgkin's lymphoma

Heterologous Expression of the Transcriptional Regulator Escargot Inhibits Megakaryocytic Endomitosis

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