Innate Apoptosis of Human B Lymphoblasts Transformed by Epstein-Barr Virus: Modulation by Cellular Immortalization and Senescence.

Satoh, Misako; Yasuda, Tatsuya; Higaki, Toru; Goto, Makoto; Tanuma, Sei–ichi; Ide, Toshinori; Furuichi, Yasuhiro; Sugimoto, Masanobu

doi:10.1247/csf.28.61

Cited by 11 publications

(8 citation statements)

References 19 publications

(29 reference statements)

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“…4C). It was not a surprise that even normal transformed cells were relatively resistant to apoptosis: this has been shown in EBV-transformed and immortalized B lymphoblastoid cell lines (33,34) and for CH11-induced apoptosis in tumor cells from non-Hodgkin's lymphoma (46). PD98059 ( Fig.…”

Section: Discussionmentioning

confidence: 81%

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PRKAR1A Inactivation Leads to Increased Proliferation and Decreased Apoptosis in Human B Lymphocytes

et al. 2006

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The multiple neoplasia syndrome Carney complex (CNC) is caused by heterozygote mutations in the gene, which codes for the RIA regulatory subunit (PRKAR1A) of protein kinase A. Inactivation of PRKAR1A and the additional loss of the normal allele lead to tumors in CNC patients and increased cyclic AMP signaling in their cells, but the oncogenetic mechanisms in affected tissues remain unknown. Previous studies suggested that PRKAR1A down-regulation may lead to increased mitogen-activated protein kinase (MAPK) signaling. Here, we show that, in lymphocytes with PRKAR1A-inactivating mutations, there is increased extracellular signal-regulated kinase (ERK) 1/2 and B-raf phosphorylation and MAPK/ERK kinase 1/2 and c-Myc activation, whereas c-Raf-1 is inhibited. These changes are accompanied by increased cell cycle rates and decreased apoptosis that result in an overall net gain in proliferation and survival. In conclusion, inactivation of PRKAR1A leads to widespread changes in molecular pathways that control cell cycle and apoptosis. This is the first study to show that human cells with partially inactivated RIA levels have increased proliferation and survival, suggesting that loss of the normal allele in these cells is not necessary for these changes to occur. (Cancer Res 2006; 66(21): 10603-12)

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Section: Discussionmentioning

confidence: 81%

“…4A). Therefore, both nl-tBls and mt-tBls were more resistant to staurosporine-induced apoptosis than Jurkat cells, most likely an effect of EBV transformation of these cells (33,34). Nevertheless, apoptosis by this mechanism was significantly less in mt-tBls.…”

Section: Resultsmentioning

confidence: 94%

PRKAR1A Inactivation Leads to Increased Proliferation and Decreased Apoptosis in Human B Lymphocytes

et al. 2006

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“…A large proportion of LCL cells spontaneously differentiate into smaller lymphoid cells that ultimately undergo apoptosis during conventional cell culture (35). Two distinct types of apoptosis with intermediate types exist: type 1 apoptosis in small and medium cells accompanied by relatively large internucleosomally fragmented DNA (greater than 2 kbp); and type 2 apoptosis in large lymphoblasts accompanied by smaller internucleosomally fragmented DNA (less than 2 kbp).…”

Section: Modification Of Apoptosis By Cellular Senescence and Tumorigmentioning

confidence: 99%

“…Two distinct types of apoptosis with intermediate types exist: type 1 apoptosis in small and medium cells accompanied by relatively large internucleosomally fragmented DNA (greater than 2 kbp); and type 2 apoptosis in large lymphoblasts accompanied by smaller internucleosomally fragmented DNA (less than 2 kbp). The morphological differentiation of LCL cells into small lymphoid cells leading to type 1 apoptosis is almost completely blocked in the tumorigenic post-immortal N6803 cell line, as judged by morphological study of smeared cells stained with Giemsa and by analysis with a cell sorter (35,37). This fact also suggests that the post-immortal LCL N6803 is an undifferentiated type.…”

Section: Modification Of Apoptosis By Cellular Senescence and Tumorigmentioning

confidence: 99%

Steps Involved in Immortalization and Tumorigenesis in Human B-Lymphoblastoid Cell Lines Transformed by Epstein-Barr Virus

Sugimoto

Tahara²,

Ide³

et al. 2004

Cancer Research

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131

138

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“…11,13,14) Postimmortal LCLs undergo other changes during long-term culture [15][16][17] : down-regulation of p16/Rb, mutation of the p53 gene, modulation of apoptosis and sensitivity to chemical agents. Some post-immortal LCLs develop the ability to form colonies in agarose, and even become tumorigenic by developing the ability to grow in nude mice.…”

mentioning

confidence: 99%

Differential Cytotoxicity of Anticancer Agents in Pre- and Post-Immortal Lymphoblastoid Cell Lines

Sawada

Nöda

Nakajima

et al. 2005

Biological & Pharmaceutical Bulletin

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An anticancer drug screening program based on the use of multiple panels of human solid tumor cell lines was developed in the United States, 1) and a similar system using a panel of 60 human tumor cell lines organized into subpanels representing leukemia, melanoma, and cancers of the lung, colon, kidney, ovary, and central nervous system was also developed. 2) Vassilev et al.3) used a cell-based screening approach for anticancer drugs by using sensitivity differences between normal and cancer cells. For these studies, diploid adherent cells-if used, including fibroblasts, are mainly used as a control cell line. A potential problem in these systems is that most control cells do not necessarily have a high proliferating activity, and do not show a high sensitivity to anticancer agents. Anticancer agents have strong side effects in actively proliferating cells, such as haemapoietic cells, lymphoid cells, gut epithelial cells and hair root cells causing anemia, lymphopenia, diarrhea, and loss of hair. Therefore, easily available control cell lines with actively proliferating activity are required.Human resting B-cells from peripheral blood are easily transformed by Epstein-Barr virus (EBV) to actively proliferating lymphoblastoid cell lines (LCLs). These LCLs with normal diploid karyotypes have long been believed to be "immortal", without becoming tumorigenic. [4][5][6] A series of recent studies, however, indicate that this initial, simple concept needs extensive reconsideration.7-11) Most conventionally established LCLs from normal individuals are mortal (pre-immortal) because their telomeres shorten.12) Some LCLs are truly immortalized (post-immortal) by overcoming the proliferation crisis, accompanied by developing strong telomerase activity and abnormal chromosomes including aneuploidy, after chromosomal rearrangement. 11,13,14) Postimmortal LCLs undergo other changes during long-term culture [15][16][17] : down-regulation of p16/Rb, mutation of the p53 gene, modulation of apoptosis and sensitivity to chemical agents. Some post-immortal LCLs develop the ability to form colonies in agarose, and even become tumorigenic by developing the ability to grow in nude mice. Notably, pre-immortal LCL cells share various characteristics with normal B-lymphoblasts generated in vivo by antigen stimulation, providing a basis to use pre-immortal LCLs as a control cell line representing actively proliferating normal lymphoblasts.6,18) Normal lymphoblasts and LCL cells share the following characteristics: lymphoblastoid morphology, surface immunoglobulin, secretion of immunoglobulin, a limited lifespan (mortal), negative or low telomerase activity and normal diploid chromosomes. If pre-and post-immortal LCLs derived from a common cell line show different cytotoxicity against anticancer agents, the difference is considered to be solely due to immortalization. Therefore, we used post-immortal LCLs (post-LCLs) as a model of lymphoma and pre-immortal LCLs (pre-LCLs) as a control.Anticancer agents are roughly divided into two group...

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Innate Apoptosis of Human B Lymphoblasts Transformed by Epstein-Barr Virus: Modulation by Cellular Immortalization and Senescence.

Cited by 11 publications

References 19 publications

PRKAR1A Inactivation Leads to Increased Proliferation and Decreased Apoptosis in Human B Lymphocytes

PRKAR1A Inactivation Leads to Increased Proliferation and Decreased Apoptosis in Human B Lymphocytes

Steps Involved in Immortalization and Tumorigenesis in Human B-Lymphoblastoid Cell Lines Transformed by Epstein-Barr Virus

Differential Cytotoxicity of Anticancer Agents in Pre- and Post-Immortal Lymphoblastoid Cell Lines

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