Bcl-2 expression delays mammary tumor development in dimethylbenz(a)anthracene-treated transgenic mice

Murphy, Kristen L; Kittrell, Frances; Jäger, Richard; Medina, Daniel; Rosen, Jeffrey M.

doi:10.1038/sj.onc.1203099

Cited by 49 publications

(37 citation statements)

References 20 publications

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“…Overexpression of Bcl-2 in leukemia cells, lymphocytes and other mammalian cells inhibits cellcycle entry (Pietenpol et al, 1994;Brady et al, 1996;Linette et al, 1996;Mazel et al, 1996;O'Reilly et al, 1996;Vairo et al, 1996;Huang et al, 1997). In a mouse mammary tumor model, Bcl-2 expression delays tumor progression (Murphy et al, 1999), consistent with clinical observations showing that high levels of Bcl-2 protein are associated with favorable prognosis in breast cancer patients (Jager et al, 2002). Additionally, co-expression of Bcl-2 specifically suppressed c-Myc-induced hepatocarcinoma in transgenic mice (de La Coste et al, 1999).…”

Section: Introductionsupporting

confidence: 80%

Identification of an ataxia telangiectasia-mutated protein mediated surveillance system to regulate Bcl-2 overexpression

et al. 2006

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Bcl-2 can both promote and attenuate tumorigenesis. Although the former function is relatively well characterized, the mechanism of the latter remains elusive. We report here that enforced Bcl-2 expression in MCF7 cells stabilizes p53, induces phosphorylation of p53 serine 15 (p53pSer15) and inhibits MCF7 cell growth. Consistent with p53 Ser15 being a target of ataxia telangiectasia mutated protein(ATM)/ATR (ATM-and rad3-related) in the DNA damage response, Bcl-2 activates ATM by inducing ATM Ser1981 phosphorylation, which is accompanied with the phosphorylaton of two additional ATM substrates, Chk2 Thr68 and H2AX Ser139. Downregulation of ATM using a specific small interference RNA fragment (ATMRNAi) abolished Bcl-2-induced p53pSer15 and Bcl-2-mediated growth inhibition of MCF7 cells. Ectopic expression of a dominant-negative p53 mutant, p53175H, partially rescued this growth inhibition. Taken together, these observations demonstrate the contribution of ATM-p53 function to Bcl-2-mediated inhibition of MCF7 cell growth, indicating an ATM-mediated surveillance system for regulating Bcl-2 overexpression. Consistent with this concept, we found that MCF7 cells express Bcl-2 heterogeneously with 34.5% of cells being Bcl-2 negative. In general, Bcl-2-positive MCF7 cells proliferate slower than those of Bcl-2 negative. Thus, we provide evidence suggesting that activation of ATM suppresses Bcl-2-induced tumorigenesis, and that attenuation of ATM function may be an important event in breast cancer progression.

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Section: Introductionsupporting

confidence: 80%

Identification of an ataxia telangiectasia-mutated protein mediated surveillance system to regulate Bcl-2 overexpression

et al. 2006

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“…30 In WAP-TAg and carcinogen-driven mammary tumor models, in which stages of initial proliferation and progression are obvious, BCL2 expression reduces both proliferation and apoptosis early in the process, but the antiproliferative effect is lost as tumors progress to adenocarcinoma. 31,32 Association of BCL2 with differentiated phenotypes and better prognosis is borne out in human breast cancer studies. 33 In the classical two-stage skin carcinogenesis model, BCL2 expression in basal epidermal keratinocytes similarly increased the latency and reduced the frequency of papillomas converting to malignant carcinomas.…”

Section: Bcl2 Cell Cycle Control and Tumorigenesismentioning

confidence: 99%

BCL2 family in DNA damage and cell cycle control

2006

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Individual BCL2 family members couple apoptosis regulation and cell cycle control in unique ways. Antiapoptotic BCL2 and BCL-x L are antiproliferative by facilitating G0. BAX is proapoptotic and accelerates S-phase progression. The dual functions in apoptosis and cell cycle are coordinately regulated by the multi-domain BCL2 family members (MCL-1) and suggest that survival is maintained at the expense of proliferation. The role of BH3-only molecules in cell cycle is more variable. BAD antagonizes both the cell cycle and antiapoptotic functions of BCL2 and BCL-x L through BH3 binding. BID has biochemically separable functions in apoptosis and S-phase checkpoint, determined by posttranslational modification. p53-induced PUMA is known only to have apoptotic function. Inhibition of apoptosis is oncogenic, whereas promotion of cell cycle arrest is tumor suppressive. Paradoxically, selected BCL2 family members can be both oncogenic and tumor suppressive. Which of the dual functions predominates is lineage specific and context dependent.

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“…The capacity of Bcl-2 to inhibit Cdk2 via p27 KIP1 up-regulation may well justify its tumour-suppressive activity, which has been demonstrated in several models of in vivo carcinogenesis [13][14][15][16]. We propose that the observed down-regulation of Bcl-2 during human carcinoma development, as well as the association of Bcl-2 protein with a favourable prognosis and increased patient survival, are related to the ability of Bcl-2 to severely affect the proliferation of carcinoma cells and to induce premature senescence.…”

Section: Role Of Bcl-2-dependent Cell-cycle Regulation and Implicatiomentioning

confidence: 99%

“…However, evidence exists to suggest that Bcl-2 can have a pronounced anti-mitotic effect on continuously cycling tumour cells [7,12]. This anti-proliferative property has been used to explain the putative tumour-suppressor activity of Bcl-2, which has been observed in transgenic mouse models of the mammary gland [13,14] and hepatic carcinogenesis [15,16]. In addition, elevated Bcl-2 levels have been associated with both a reduced proliferation rate and favourable prognosis in several human carcinomas, and a selective down-regulation of Bcl-2 has been observed during tumour progression in various human cancers [17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Bcl-2 activates a programme of premature senescence in human carcinoma cells

Crescenzi

Palumbo

Brady

2003

Biochemical Journal

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The apoptosis regulator Bcl-2 has been shown to modulate cellcycle progression, favouring a quiescent state over a proliferative state, in both normal and tumour cells. We show here that constitutive expression of Bcl-2 in human carcinoma cells results in a cell-cycle arrest that within a few days can become irreversible. Arrested cells acquire a senescent-like phenotype, which consists of several characteristic morphological alterations and increased activity of senescence-associated β-galactosidase. The induction of the premature senescence programme is mediated by inhibition of Cdk2 kinase activity, and p27 KIP1 is required to maintain the senescent phenotype. We propose that the ability to activate an endogenous premature senescence programme allows Bcl-2 to suppress tumour growth. These results suggest that the downregulation of Bcl-2 expression, which has been observed during the development and progression of human carcinoma, is related to the ability of Bcl-2 to severely hamper the growth of carcinoma cells and to induce a permanent cell-cycle arrest, with the features of senescence.

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Bcl-2 expression delays mammary tumor development in dimethylbenz(a)anthracene-treated transgenic mice

Cited by 49 publications

References 20 publications

Identification of an ataxia telangiectasia-mutated protein mediated surveillance system to regulate Bcl-2 overexpression

Identification of an ataxia telangiectasia-mutated protein mediated surveillance system to regulate Bcl-2 overexpression

BCL2 family in DNA damage and cell cycle control

Bcl-2 activates a programme of premature senescence in human carcinoma cells

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