Transcriptional silencing of Polo-like kinase 2<i>(SNK/PLK2)</i>is a frequent event in B-cell malignancies

Syed, Nelofer; Smith, Paul J.; Sullivan, Alice; Spender, Lindsay C.; Dyer, Martin J. S.; Karran, Lorraine; O’Nions, Jenny; Allday, Martin J.; Hoffmann, Ingrid; Crawford, Dorothy H.; Griffin, Beverly E.; Farrell, Patrick J.; Crook, Tim

doi:10.1182/blood-2005-03-1194

Cited by 115 publications

(141 citation statements)

References 23 publications

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“…In central neurons, PLK2 was reported to be overexpressed in response to synaptic stimulation (9). Decreased expression of PLK2 was observed in B-cell malignancies; in addition, apoptosis was found to be induced in Burkitt's lymphoma cells through the ectopic expression of PLK2 (10). This therefore indicated that PLK2 may act as a tumor suppressor gene in hematologic malignancies (10,11).…”

Section: Introductionmentioning

confidence: 78%

“…Decreased expression of PLK2 was observed in B-cell malignancies; in addition, apoptosis was found to be induced in Burkitt's lymphoma cells through the ectopic expression of PLK2 (10). This therefore indicated that PLK2 may act as a tumor suppressor gene in hematologic malignancies (10,11). Pellegrino et al (12) showed that PLK2 was a tumor suppressor in hepatocarcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Silencing of polo-like kinase 2 increases cell proliferation and decreases apoptosis in SGC-7901 gastric cancer cells

Liu

Wang

Zhao

et al. 2014

Molecular Medicine Reports

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Abstract. Polo-like kinase 2 (PLK2) is a serine/threonine protein kinase, which has vital roles during mitosis and the centrosome cycle. In acute myeloblastic leukemia and hepatocarcinogenesis, PLK2 acts as a tumor suppressor; however, the function of PLK2 in gastric cancer remains to be elucidated. In the present study, PLK2 was overexpressed in gastric cancer tissues and three types of gastric cancer cells, SGC-7901, MKN-45 and BGC-823. Transfection of SGC-7901 gastric cancer cells with small interfering (si)RNA against PLK2 exerted no effect on the ratio of cells at different stages of the cell cycle compared with that of the untransfected and control siRNA-transfected cells. In addition, silencing of PLK2 significantly enhanced the growth of SGC-7901 cells through inhibiting apoptosis. Furthermore, apoptosis-associated genes Bax and caspase 3 were found to be downregulated at the protein level. In conclusion, these results suggested that PLK2 may act as a tumor suppressor in gastric cancer, therefore indicating its therapeutic potential. IntroductionGastric cancer, also known as stomach cancer, has a high incidence rate in and is one of the most prominent causes of cancer-associated mortality in Asia (1). In addition, gastric cancer is the fourth most prevalent type of cancer worldwide and the second most frequent cause of cancer-associated mortality worldwide (2,3). The prognosis of gastric cancer patients is poor and it remains challenging to cure. Targeted gene therapy is a novel therapeutic approach for gastric cancer, for which the identification of tumor suppressors associated with this malignancy is essential.Polo-like kinase 2 (PLK2) is a member of the serine/threonine protein kinase family, which includes five members: PLK1, PLK2 (also termed SNK), PLK3 (also termed Fnk or Prk), PLK4 (also termed Sak) and PLK5 (4-6). These kinases have important roles during mitosis and the centrosome cycle (7). PLK2 is located in the centrosome and was found to be involved in embryonic development and cell cycle progression at the G 1 /S transition, as well as in skeletal development. Cell cycle analysis of cultured PLK2 -/-embryonic fibroblasts indicated that these cells proliferated more slowly than cells expressing PLK2 and exhibited delayed entry into S phase from G 1 (8). In central neurons, PLK2 was reported to be overexpressed in response to synaptic stimulation (9). Decreased expression of PLK2 was observed in B-cell malignancies; in addition, apoptosis was found to be induced in Burkitt's lymphoma cells through the ectopic expression of PLK2 (10). This therefore indicated that PLK2 may act as a tumor suppressor gene in hematologic malignancies (10,11). Pellegrino et al (12) showed that PLK2 was a tumor suppressor in hepatocarcinogenesis. In addition, Kothari et al (13) reported that PLK2 is an outlier kinase, which was highly expressed in Silencing of polo-like kinase 2 increases cell proliferation and decreases apoptosis in SGC-7901 gastric cancer cells

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Section: Introductionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Silencing of polo-like kinase 2 increases cell proliferation and decreases apoptosis in SGC-7901 gastric cancer cells

Liu

Wang

Zhao

et al. 2014

Molecular Medicine Reports

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“…PLK2 transcription is regulated by p53, but interestingly, the p53 binding sites in the PLK2 gene display both stimulatory and inhibitory elements, suggesting more complex interactions between PLK2 and this wellestablished tumor suppressor (22,29,30). PLK2 has also been shown to be epigenetically silenced in high grade B-cell lymphomas, implicating it as a tumor suppressor; however, this phenomenon appears to be limited to malignant B cells (31). In contrast to some established tumor suppressor genes, somatic mutations in PLK2 have not been identified in primary human cancers, which in some cases express higher levels of PLK2 compared to normal tissues (23,31,32).…”

Section: Discussionmentioning

confidence: 99%

“…PLK2 has also been shown to be epigenetically silenced in high grade B-cell lymphomas, implicating it as a tumor suppressor; however, this phenomenon appears to be limited to malignant B cells (31). In contrast to some established tumor suppressor genes, somatic mutations in PLK2 have not been identified in primary human cancers, which in some cases express higher levels of PLK2 compared to normal tissues (23,31,32). These varying observations suggest that the role of PLK2 in tumorigenesis may depend on cell type and context.…”

Section: Discussionmentioning

confidence: 99%

Polo-like kinases mediate cell survival in mitochondrial dysfunction

Matsumoto

Wang

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Cancer cells often display defects in mitochondrial respiration, thus the identification of pathways that promote cell survival under this metabolic state may have therapeutic implications. Here, we report that the targeted ablation of mitochondrial respiration markedly increases expression of Polo-like kinase 2 (PLK2) and that it is required for the in vitro growth of these nonrespiring cells. Furthermore, we identify PLK2 as a kinase that phosphorylates Ser-137 of PLK1, which is sufficient to mediate this survival signal. In vivo, knockdown of PLK2 in an isogenic human cell line with a modest defect in mitochondrial respiration eliminates xenograft formation, indicating that PLK2 activity is necessary for growth of cells with compromised respiration. Our findings delineate a mitochondrial dysfunction responsive cell cycle pathway critical for determining cancer cell outcome.cell cycle ͉ respiration ͉ sco2

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“…More specifically, they showed that this methylation-dependent silencing occurs with very high frequency in BL (n ϭ 24/25). On this basis, they suggest that BL may be a particularly good target for taxane-like drugs (28).…”

Section: Discussionmentioning

confidence: 99%

Epstein-Barr Virus-Induced Resistance to Drugs That Activate the Mitotic Spindle Assembly Checkpoint in Burkitt's Lymphoma Cells

Leão

Anderton

Wade

et al. 2007

J Virol

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Epstein-Barr virus (EBV)is associated with a number of human cancers, and latent EBV gene expression has been reported to interfere with cell cycle checkpoints and cell death pathways. Here we show that latent EBV can compromise the mitotic spindle assembly checkpoint and rescue Burkitt's lymphoma (BL)-derived cells from caspase-dependent cell death initiated in aberrant mitosis. This leads to unscheduled mitotic progression, resulting in polyploidy and multi-and/or micronucleation. The EBV latent genes responsible for this phenotype are expressed from the P3HR1 strain of virus and several viruses with similar genomic deletions that remove the EBNA2 gene. Although EBNA2 and the latent membrane proteins are not expressed, the EBNA3 proteins are present in these BL cells. Survival of the EBV-positive cells is not consistently associated with EBV lytic gene expression or with the genes that are expressed in EBV latency I BL cells (i.e., EBNA1, EBERs, and BARTs) but correlates with reduced expression of the cellular proapoptotic BH3-only protein Bim. These data suggest that a subset of latent EBV gene products may increase the likelihood of damaged DNA being inherited because of the impaired checkpoint and enhanced survival capacity. This could lead to greater genetic diversity in progeny cells and contribute to tumorigenesis. Furthermore, since it appears that this restricted latent EBV expression interferes with the responses of Burkitt's lymphoma-derived cells to cytotoxic drugs, the results of this study may have important therapeutic implications in the treatment of some BL. Epstein-Barr virus (EBV) is a gammaherpesvirus that pro-duces an asymptomatic infection in the majority of the human population. However, EBV is also associated with a number of human tumors of B-cell, T-cell, and epithelial origin. These include Burkitt's lymphoma (BL), some types of Hodgkin's lymphoma, immunoblastic B lymphoma in the immunosuppressed, nasopharyngeal carcinoma, and gastric carcinoma. Although the precise contribution EBV makes to the development of these diseases is not yet known, it has been suggested that interference with cell cycle checkpoints and cell death pathways by EBV may play an important role in B lymphomagenesis (reviewed in reference 20).In vitro, EBV has the ability to infect and transform primary B cells into continuously proliferating lymphoblastoid cell lines (LCLs) that have a pattern of viral gene expression known as latency III. This is characterized by the expression of nine viral proteins: six Epstein-Barr nuclear antigens (EBNAs) (EBNA1, -2, -3A, -3B, -3C, and -LP) and three latent membrane proteins (LMPs) (LMP1, -2A, and -2B). Additional RNA species (the EBV-encoded RNAs [EBERs] and the BamHIA rightward transcripts [BARTs]) are also expressed during latency III, but their significance is not fully understood (3). It has been reported from studies with recombinant EBV that only six of the latency III proteins (EBNA1, -2, -3A, -3C, -LP, and -LMP1) are essential for efficient transformation of B cells...

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Transcriptional silencing of Polo-like kinase 2(SNK/PLK2)is a frequent event in B-cell malignancies

Cited by 115 publications

References 23 publications

Silencing of polo-like kinase 2 increases cell proliferation and decreases apoptosis in SGC-7901 gastric cancer cells

Silencing of polo-like kinase 2 increases cell proliferation and decreases apoptosis in SGC-7901 gastric cancer cells

Polo-like kinases mediate cell survival in mitochondrial dysfunction

Epstein-Barr Virus-Induced Resistance to Drugs That Activate the Mitotic Spindle Assembly Checkpoint in Burkitt's Lymphoma Cells

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