Apoptosis Inhibitor as a Suppressor of Tumor Progression: Expression of Bcl-2 Eliminates Selective Advantages for p53-Deficient Cells in the Tumor

Gurova, Katerina V.; Kwek, Serena S.; Koman, Igor; Komarov, Andrei P.; Kandel, Eugene; Nikiforov, Mikhail A.; Gudkov, Andrei V.

doi:10.4161/cbt.1.1.39

Cited by 27 publications

(15 citation statements)

References 20 publications

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“…In this study, we found that Bcl-2 blocked Bax-induced aneuploidy in p53+/+ mice. These effects could be explained by the retention of wild-type p53 in cells expressing Bcl-2 as has been observed in other models (17,(35)(36)(37). However, this simple model does not fully explain the paradoxical effects observed in our studies.…”

Section: Discussioncontrasting

confidence: 50%

Chromosomal Instability and Supernumerary Centrosomes Represent Precursor Defects in a Mouse Model of T-Cell Lymphoma

Wetering

Knudson²

2007

Cancer Research

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A hallmark of carcinogenesis is resistance to cell death. However, recent studies indicate that Bax expression increased apoptosis and promoted oncogenesis. In this study, we hypothesized that Bax promotes tumor formation by increasing chromosomal instability (CIN). Consistent with this hypothesis, spectral karyotype analysis (SKY) of lymphomas derived from Lck-Bax38/1 mice were consistently aneuploid. To determine if CIN precedes tumor formation, quantitative cytogenetic analysis, SKY analysis, and quantitative centrosome staining were done on thymocytes from young premalignant mice. Between 6 and 10 weeks of age, thymi from Bax-expressing mice (either p53+/+ or p53À/À) had an increased percentage of aneuploid cells as well as an increase in cells with supernumerary centrosomes. For 3-to 6-weekold mice, Bax expression increased aneuploidy and supernumerary centrosomes in p53À/À mice but not in p53+/+ animals. Importantly, both aneuploidy and supernumerary centrosomes were attenuated by Bcl-2. Remarkably, SKY analysis showed multiple independent aneuploid populations in the p53À/À Bax-expressing mice between 3 and 6 weeks of age. These results indicate that oligoclonal aneuploidy and supernumerary centrosomes are early hallmarks of Baxinduced lymphoma formation and support a novel link between the Bcl-2 family and CIN. The data provide an attractive model for the paradoxical effects of the Bcl-2 family on carcinogenesis that have been observed in multiple studies of both humans and mice. [Cancer Res 2007;67(17):8081-8]

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Section: Discussioncontrasting

confidence: 50%

Chromosomal Instability and Supernumerary Centrosomes Represent Precursor Defects in a Mouse Model of T-Cell Lymphoma

Wetering

Knudson²

2007

Cancer Research

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“…Indeed, it has been suggested recently that the acquisition of aneuploidy does not constitute a critical tumorigenic determinant of p53 loss in the E-myc lymphoma model (56,57). However, although cells derived from Kaposi's sarcomas or primary effusion lymphoma seldom display overt ploidy changes (see examples in Refs.…”

Section: Discussionmentioning

confidence: 99%

The Role of p53 in Suppression of KSHV Cyclin-induced Lymphomagenesis

et al. 2004

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Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a cyclin D homolog, K cyclin, that is thought to promote viral oncogenesis. However, expression of K cyclin in cultured cells not only triggers cell cycle progression but also engages the p53 tumor suppressor pathway, which probably restricts the oncogenic potential of K cyclin. Therefore, to assess the tumorigenic properties of K cyclin in vivo, we transgenically targeted expression of K cyclin to the B and T lymphocyte compartments via the E promoter/enhancer. Around 17% of E-K cyclin animals develop lymphoma by 9 months of age, and all such lymphomas exhibit loss of p53. A critical role of p53 in suppressing K cyclin-induced lymphomagenesis was confirmed by the greatly accelerated onset of B and T lymphomagenesis in all E-K cyclin/p53 ؊/؊ mice. However, absence of p53 did not appear to accelerate K cyclin-induced lymphomagenesis by averting apoptosis: E-K cyclin/p53 ؊/؊ end-stage lymphomas contained abundant apoptotic cells, and transgenic E-K cyclin/p53 ؊/؊ lymphocytes in vitro were not measurably protected from DNA damage-induced apoptosis compared with E-K cyclin/p53 wt cells. Notably, whereas aneuploidy was frequently evident in pre-lymphomatous tissues, end-stage E-K cyclin/ p53 ؊/؊ tumors showed a near-diploid DNA content with no aberrant centrosome numbers. Nonetheless, such tumor cells did harbor more restricted genomic alterations, such as single-copy chromosome losses or gains or high-level amplifications. Together, our data support a model in which K cyclin-induced genome instability arises early in the pre-tumorigenic lymphocyte population and that loss of p53 licenses subsequent expansion of tumorigenic clones.

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“…One could argue that slower growth of tumors in bcl-2 transgenic mice might be the result of anti-proliferative effect of bcl-2. However, this difference is likely to be the reflection of slower progression of these tumors rather than a direct effect of bcl-2 overexpression: introduction of bcl-2 into tumorigenic cell lines usually results in development of faster growing tumors [Kajiwara et al, 1999;Gurova et al, 2002].…”

Section: Bcl-2 As An Anti-progressor: Lessons From Experimental Modelsmentioning

confidence: 99%

“…To directly check how tumor progression depends on apoptosis sensitivity of the original tumor, we created tumor cell population differing in their apoptotic potential and monitored the expansion of ''more malignant'' rare variants inside such tumors in vivo [Gurova et al, 2002]. As ''a more malignant variants, we used cells either with inactivated p53 or with overexpressed bcl-2, both resistant to DNA damaging agents and hypoxia due to suppression of apoptosis.…”

Section: Crucial Experiment: Bcl-2 Prevents Selection Of Genetically mentioning

confidence: 99%

“…To clarify this problem, we directly compared the effects of Bcl-2 overexpression and p53 inactivation, both resulting in suppression of apoptosis, on the genetic stability determined by a standard assay based on a frequency of CAD gene amplification in cell population maintained in constant presence of CAD protein inhibitor PALA [Gurova et al, 2002]. The results of these experiments came as a surprise: while p53 suppression had an expected effect, causing several orders of magnitude-fold increase in the frequency of gene amplification, ectopic expression of bcl-2 (that was enough to suppress apoptosis) did not result in a detectable change in genomic stability.…”

Section: Anti-progressor Function Of Apoptosis: a Hypothetical Modelmentioning

confidence: 99%

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Paradoxical role of apoptosis in tumor progression

Gurova

Gudkov

2002

J of Cellular Biochemistry

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Tumors frequently acquire resistance to apoptosis that is expected to contribute to malignant phenotype and reduce sensitivity to treatment. In fact, inactivation of p53 tumor suppressor gene resulting in suppression of apoptosis serves as a negative prognostic marker. Surprisingly, expression of a strong anti-apoptotic protein Bcl-2, another mechanism to avoid apoptosis, was found to be associated with a favorable prognosis. This paradoxical anti-progressor function of Bcl-2 has been explained in literature based on the negative effect of Bcl-2 on cell proliferation. Here, by analyzing accumulated experimental and clinical data, we provide evidence supporting another hypothesis that defines apoptosis as an accelerator of tumor progression. The mechanism of anti-progressor function of Bcl-2 is based on creation of tumors that maintain control of genomic stability by eliminating selective advantages for the cells that acquire resistance to apoptosis through loss of p53. Thus, inhibition of apoptosis does not lead to loss of genomic stability and creates tumor environment that no longer supports further tumor progression and inhibitors of apoptosis can be considered as factors suppressing tumor progression.

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Apoptosis Inhibitor as a Suppressor of Tumor Progression: Expression of Bcl-2 Eliminates Selective Advantages for p53-Deficient Cells in the Tumor

Cited by 27 publications

References 20 publications

Chromosomal Instability and Supernumerary Centrosomes Represent Precursor Defects in a Mouse Model of T-Cell Lymphoma

Chromosomal Instability and Supernumerary Centrosomes Represent Precursor Defects in a Mouse Model of T-Cell Lymphoma

The Role of p53 in Suppression of KSHV Cyclin-induced Lymphomagenesis

Paradoxical role of apoptosis in tumor progression

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