Deregulated transcription factor E2F-1 expression leads to S-phase entry and p53-mediated apoptosis.

Qin, Xiao Qiang; Livingston, David M.; Kaelin, William G.; Adams, Peter D.

doi:10.1073/pnas.91.23.10918

Cited by 690 publications

(586 citation statements)

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“…After removal of¯oating cells,¯at cells remaining on the plate did not express NPM-MLF1 proteins. Aequorea green¯uorescent protein (GFP) (Ogawa et al, 1995) was used as a transfection marker to comparatively analyse the kinetics of apoptosis induced by ectopic overexpression of NPM-MLF1, cMyc or E2F-1 (Evan et al, 1992;Askew et al, 1991;Wu and Levine, 1994;Qin et al, 1994;Shan and Lee, 1994) followed by serum starvation. Figure 2b shows that NPM-MLF1 transfectants died gradually during 72 h after serum starvation, while most of the c-Myc and E2F-1 transfectants rapidly lost their viability within 24 h. These observations indicate that ectopic overexpression of NPM-MLF1 in mouse ®broblasts induced apoptotic cell death upon serum deprivation with slower kinetics than did other well-known apoptotic inducers such as c-Myc or E2F-1.…”

Section: Resultsmentioning

confidence: 99%

“…Other apoptotic inducers such as c-Myc and E2F-1 also promote S phase entry (Evan et al, 1992;Askew et al, 1991;Wu and Levine, 1994;Qin et al, 1994;Shan and Lee, 1994), but accelerated initiation of DNA replication itself does not trigger apoptotic pathways (Hsieh et al, 1997;Phillips et al, 1997). For example, other E2F family members (E2F-2 and -3) induce S phase entry of serum-starved ®broblasts without evoking apoptosis (DeGregori et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

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Apoptosis induced by the myelodysplastic syndrome-associated NPM-MLF1 chimeric protein

1999

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The NPM-MLF1 chimeric protein is produced by the t(3;5)(q25.1;q34) chromosomal translocation, which is associated with myelodysplastic syndrome (MDS) prior to progression into acute myeloid leukemia (AML). Here we report that K562 human leukemia cells ectopically expressing NPM-MLF1, but not those with wild-type MLF1, were gradually eliminated from the culture by undergoing apoptosis. NIH3T3 mouse ®broblasts engineered to overexpress NPM-MLF1 grew normally but serum deprivation triggered apoptotic cell death with slower kinetics than did other well-known apoptotic inducers such as c-Myc or E2F-1. Quantitative analysis of apoptotic induction con®rmed that, neither NPM nor MLF1, but the NPM-MLF1 fusion protein was able to induce apoptosis. Analyses using a variety of deletion mutants of NPM-MLF1 revealed that induction of apoptosis required the N-terminal domain of MLF1 and the NPM domain containing nuclear localization signal and that removal of the NPM dimerization domain markedly impaired the ability to induce apoptosis. Co-expression of Bcl-2 rescued NIH3T3 ®broblasts from NPM-MLF1-mediated cell death without a ecting the expression level or the subcellular localization of NPM-MLF1 and enabled cells to progress into S phase in low serum. These ®ndings provide an NPM-MLF1-mediated novel mechanism of apoptotic induction and imply that NPM-MLF1 in collaboration with anti-apoptotic oncoproteins may play an important role in multi-step progression from MDS to AML.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Apoptosis induced by the myelodysplastic syndrome-associated NPM-MLF1 chimeric protein

1999

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“…The mechanisms by which Rb may directly exert its anti-apoptotic activities are still poorly understood. It has recently been reported that deregulated expression of Rb binding proteins such as E2F-1 can promote apoptosis (Qin et al, 1994;Shan and Lee, 1994;Wu and Levine, 1994). However, the role of the Rb binding molecules during the TGFb-mediated apoptosis has not yet been elucidated.…”

Section: Discussionmentioning

confidence: 99%

Role of caspases and possible involvement of retinoblastoma protein during TGFβ-mediated apoptosis of human B lymphocytes

et al. 1999

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In this study, we investigated the involvement of caspases in TGFb-induced apoptosis in human B cells. Our results show that TGFb-mediated nuclear fragmentation, observed in the Epstein ± Barr virus-negative Burkitt's Lymphoma cell line BL41, was abolished in the presence of the tripeptide caspase inhibitor ZVAD-fmk or the speci®c caspase-3 inhibitor DEVD-fmk. Other apoptotic manifestations such as cell shrinkage, surface phosphatidylserine expression and chromatin condensation were strongly inhibited by ZVAD-fmk but only partially by DEVD-fmk. This suggests that other caspases in addition to caspase-3 control these apoptotis-associated features. Speci®c activation of caspase-3 during TGFbinduced apoptosis was demonstrated by the DEVD-fmksensitive expression of the active p17 subunit of caspase-3 and by in vivo cleavage of PARP. In addition, TGFb treatment of BL41 promoted the expression of both dephosphorylated and truncated forms of the retinoblastoma protein. Inhibition of caspase-3 activity abolished both nuclear fragmentation and expression of the truncated retinoblastoma protein, without modifying the G1 cell cycle arrest induced by TGFb. Our data thus demonstrate that TGFb-induced apoptosis of lymphoma B lymphocytes is dependent on caspase activation and involves caspase-dependent cleavage of the retinoblastoma protein.

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“…However, E2F1À/À knockout mice develop a broad spectrum of tumors, suggesting that E2F1 also functions as a tumor suppressor. Indeed, several authors reported that E2F1 can induce apoptosis through p53-dependent (Kowalik et al, 1995;Qin et al, 1994;Wu and Levine, 1994) and p53-independent mechanisms (Irwin et al, 2000), by upregulating apoptotic genes like Apaf-1 (Furukawa et al, 2002), p73 (Stiewe and Putzer, 2000), caspase 3 and 7 (Muller et al, 2001), Noxa and PUMA (Hershko and Ginsberg, 2004). Furthermore, forced expression of E2F1 caused increased sensitivity to DNA-damaging agents and topoisomerase II inhibition in a p53-independent manner (Nip et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Mouse double minute antagonist Nutlin-3a enhances chemotherapy-induced apoptosis in cancer cells with mutant p53 by activating E2F1

et al. 2006

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MDM2 is a critical negative regulator of the p53 tumor suppressor protein. Recently, small-molecule antagonists of MDM2, the Nutlins, have been developed to inhibit the p53-MDM2 interaction and activate p53 signaling. However, half of human cancers have mutated p53 and they are resistant to Nutlin treatment. Here, we report that treatment of the p53-mutant malignant peripheral nerve sheath (MPNST) and p53-null HCT116 cells with cisplatin (Cis) and Nutlin-3a induced a degree of apoptosis that was significantly greater than either drug alone. Nutlin-3a also increased the cytotoxicity of both carboplatin and doxorubicin in a series of p53-mutant human tumor cell lines. In the human dedifferentiated liposarcoma cell line (LS141) and the p53 wild-type HCT116 cells, Nutlin-3a induced downregulation of E2F1 and this effect appeared to be proteasome dependent. In contrast, in MPNST and HCTp53À/À cells, Nutlin-3a inhibited the binding of E2F1 to MDM2 and induced transcriptional activation of free E2F1 in the presence of Cis-induced DNA damage. Downregulation of E2F1 by small interfering RNA significantly decreased the level of apoptosis induced by Cis and Nutlin-3a treatment. Moreover, expression of a dominant-negative form of E2F1 rescued cells from apoptosis, whereas cells overexpressing wildtype E2F1 showed an increase in cell death. This correlated with the induction of the proapoptotic proteins p73a and Noxa, which are both regulated by E2F1. These results indicate that antagonism of MDM2 by Nutlin-3a in cells with mutant p53 enhances chemosensitivity in an E2F1-dependent manner. Nutlin-3a therefore may provide a therapeutic benefit in tumors with mutant p53 provided it is combined with chemotherapy.

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Deregulated transcription factor E2F-1 expression leads to S-phase entry and p53-mediated apoptosis.

Cited by 690 publications

References 50 publications

Apoptosis induced by the myelodysplastic syndrome-associated NPM-MLF1 chimeric protein

Apoptosis induced by the myelodysplastic syndrome-associated NPM-MLF1 chimeric protein

Role of caspases and possible involvement of retinoblastoma protein during TGFβ-mediated apoptosis of human B lymphocytes

Mouse double minute antagonist Nutlin-3a enhances chemotherapy-induced apoptosis in cancer cells with mutant p53 by activating E2F1

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