BCL-2 Oncogene Blocks Differentiation and Extends Viability but Does Not Immortalize Normal Human Keratinocytes

Nataraj, Arun J.; Pathak, Sen; Hopwood, Vicki L.; McDonnell, Timothy J.; Ananthaswamy, Honnavara N.

doi:10.3892/ijo.4.6.1211

Cited by 9 publications

(8 citation statements)

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“…In our previous study, we showed that Bcl-2 and LMP-1 proteins coexpressed in NPC tumor cells, and the expression of Bcl-2 and LMP-1 in NPC cells was associated with the clinical stages of NPC [36] . We also found the Bcl-2 expression efficiently inhibited LMP-1-induced apoptosis and cooperated with LMP-1 in the transformation process of epithelial cells [24] , consistent with the finding that Bcl-2 coexpression in some of LMP-1 overexpressed NPC tissues [32] . In conclusion, our results demonstrating that acquisition of constitutive Bcl-2 expression mitigates the apoptotic effects of constitutive LMP-1 overexpression without affecting the cell cycle progression, thus providing a mechanistic basis for the oncogenic synergy between LMP-1 and bcl-2 proto-oncogene.…”

Section: Discussionsupporting

confidence: 76%

“…This is an important demonstration of a potential role for Bcl-2 in carcinogenesis that was not clear from other work. Thus, the incidence of epithelial malignancies has not been reported in the bcl-2 transgenic mice [29] , and in vitro studies showed that overexpression of Bcl-2 by gene transfer was unable to immortalize epithelial cells directly [32] or transform SV40-immortalized epithelial cells [33] . Importantly, co-expression of LMP-1 and Bcl-2 has been observed in NPC [34] , strongly suggesting that the experiments described here are relevant to the pathogenesis of this EBV-positive tumor.…”

Section: Discussionmentioning

confidence: 99%

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Tumor Formation in Nude Mice Inoculated with Cultured Human Epithelial Cells Co-Expressing Epstein-Barr Virus Latent Membrane Protein 1 and Bcl-2

Lay²

2007

Intervirology

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Aims: To examine the tumor-forming in nude mice of human epithelial cells co-expressed Bcl-2 and EBV LMP-1 ability, the phenotype of tumor cells and their expression of oncogenes and tumor-suppressor genes. Methods: Following an in vivo tumorigenesis test in nude mice, the phenotype and growth properties of tumor cells were observed. Levels of expression of Bcl-2, and EBV LMP-1, and of onco- and tumor-suppressor proteins were detected by Western blot assay. Results: Human epithelial cells co-expressing Bcl-2 and EBV LMP-1 can form tumors in nude mice. Tumors appeared 48–65 days postinoculation in 6 of 10 nude mice tested but not in mice given Bcl-2-positive (0/5), LMP-1-positive (0/5) and RHEK-1 control (0/5) cells. Levels of c-myc protein were upregulated by LMP-1 but were not affected by Bcl-2 in this cell background; screening for other cellular oncogene and tumor suppressor gene products showed no change. Conclusion: The complementary effects of EBV LMP-1 and Bcl-2 in human epithelial cells resulted in tumor formation in nude mice but did not affect the expression of onco- and tumor suppressor proteins except for elevated c-myc. These findings suggest that LMP-1 and Bcl-2 can contribute together to the formation of EBV-associated epithelial cell tumors.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Tumor Formation in Nude Mice Inoculated with Cultured Human Epithelial Cells Co-Expressing Epstein-Barr Virus Latent Membrane Protein 1 and Bcl-2

Lay²

2007

Intervirology

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“…In this context, it is interesting to note that Bcl-2 expression in the skin has been shown to be restricted to the basal keratinocytes, i.e. the germinal layer of the skin [145], and that, like in lens cells, ectopic expression of Bcl-2 can block the differentiation of keratinocytes in culture [149]. It remains to be seen if a relatively simple cell death machinery in a primitive ancestral organism has evolved not only into the complex system of jurisdiction and execution of cell fate found in modern-day metazoans, but has also been used to participate in the differentiation of such specialised cell types as erythrocytes, keratinocytes and lens fibre cells.…”

Section: Discussionmentioning

confidence: 99%

Lens Fibre Cell Differentiation – A Link with Apoptosis?

Dahm¹

1999

Ophthalmic Res

101

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During the process of terminal differentiation, the fibre cells in the eye lens undergo many changes that are reminiscent of apoptotic/necrotic changes. Mitochondria, for instance, undergo permeability transition and nuclear degradation is accompanied by chromatin condensation, disintegration of the nucleolus, dissolution of the nuclear lamina, nuclear pore clustering and fragmentation of the DNA into oligonucleosomal fragments. As during apoptosis, members of the caspase family of proteases were shown to be active during fibre cell differentiation and Bcl-2 overexpression was demonstrated to block normal differentiation of lens cells. In this review, the current knowledge of the sequence of events during cell death is summarised and contrasted with events during lens fibre cell differentiation. Due to the numerous similarities between these processes, lens fibre cell differentiation is suggested to represent an attenuated form of cell death.

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“…It is well established that Bcl‐2 , a gene that protects cells from apoptosis induced by a variety of agents , 23 is expressed at the protein level in epidermal basal cells, 24 and furthermore that overexpression in cultured keratinocytes inhibits differentiation and extends viability. 25 This suggests important links in the regulation of differentiation and apoptosis. Bax (bcl‐2‐associated X protein), another member of the bcl‐2 family, promotes cell death, and low levels of the protein have been detected in all layers of the epidermis.…”

mentioning

confidence: 99%