p19ARF-induced p53-independent apoptosis largely occurs through BAX

Suzuki, Hiroaki; Kurita, Megumi; Mizumoto, Kiyohisa; Nishimoto, Ikuo; Ogata, Etsuro; Matsuoka, Masao

doi:10.1016/j.bbrc.2003.11.071

Cited by 16 publications

(13 citation statements)

References 27 publications

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“…In another recently published report, apoptosis induction by murine p19 ARF in mouse embryonic fibroblasts (MEFs) was shown to depend on Bax but not Bak and was subject to inhibition by Bcl-x L (Suzuki et al, 2003). In the same vein, we observed that the forced expression of human p14 ARF by the use of an adenoviral expression system induces apoptosis in these cells in an entirely Bax, but not Bak-dependent manner (data not shown).…”

Section: Discussionsupporting

confidence: 70%

Bak functionally complements for loss of Bax during p14ARF-induced mitochondrial apoptosis in human cancer cells

et al. 2006

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In contrast to the initial notion that the biological activity of p14 ARF strictly depends on a functional mdm-2/p53 signaling axis, we recently demonstrated that p14 ARF mediates apoptosis in a p53/Bax-independent manner. Here, we show that p14 ARF induces breakdown of the mitochondrial membrane potential and cytochrome c release before triggering caspase-9-and caspase-3/7-like activities in p53/Bax-deficient DU145 prostate cancer cells expressing wild-type Bak. Re-expression of Bax in these cells failed to further enhance p14 ARF -induced apoptosis, suggesting that p14 ARF -induced apoptosis primarily depends on Bak but not Bax in these cells. To further define the role of Bak and Bax in p14 ARF -induced mitochondrial apoptosis, we employed short interference RNA for the knockdown of bak in isogeneic, p53 wildtype HCT116 colon cancer cells either proficient or deficient for Bax. There, combined loss of Bax and Bak attenuated p14 ARF -induced apoptosis whereas single loss of Bax or Bak was only marginally effective, as in the case of DU145. Notably, HCT116 cells deficient for Bax and Bak failed to release cytochrome c and showed attenuated activation of caspase-9 (LEHDase) and caspase-3/caspase-7 (DEVDase) upon p14 ARF expression. These data indicate that p14 ARF triggers apoptosis via a Bax/Bakdependent pathway in p53-proficient HCT116, whereas Bax is dispensable in p53-deficient DU145 cells. Nevertheless, a substantial proportion of p14 ARF -induced cell death proceeds in a Bax/Bak-independent manner. This is also the case for inhibition of clonogenic growth that occurs, at least in part, through an entirely Bax/Bakindependent mechanism.

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Section: Discussionsupporting

confidence: 70%

Bak functionally complements for loss of Bax during p14ARF-induced mitochondrial apoptosis in human cancer cells

et al. 2006

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“…and Bax was observed 48 h after hydroxyurea treatment, a p53-independent mechanism may also be responsible for the induction as described previously (Johnson et al, 1994;Russo et al, 1995;Haapajarvi et al, 1999;Suliman et al, 2001;Gadducci et al, 2002;Concin et al, 2003;Suzuki et al, 2003). We next transduced cells with a retrovirus expressing Ha-Ras G12V , typically inducing 5-10-fold higher levels of Ras protein expression than empty vector (pBabe-zeo)-transduced control cells (Figure 5a and b), and increased Ras activities measured as a Raf-binding form (data not shown) within 36 h after infection.…”

Section: Waf1mentioning

confidence: 63%

Ha-RasG12V induces senescence in primary and immortalized human esophageal keratinocytes with p53 dysfunction

et al. 2004

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Oncogenic Ras induces premature senescence in primary cells. Such an oncogene-induced senescence involves activation of tumor suppressor genes that provide a checkpoint mechanism against malignant transformation. In mouse, the ARF-p53 pathway mediates Ha-Ras G12V-induced senescence, and p19 ARFÀ/À and p53 À/À cells undergo transformation upon Ras activation. In addition, mouse cells, unlike human cells, express constitutively active telomerase and have long telomeres. However, it is unclear how Ras activation affects human cells of epithelial origin with p53 mutation and/or telomerase activation. In order to address this question, Ha-Ras G12V was expressed ectopically in primary as well as hTERTimmortalized human esophageal keratinocytes stably expressing dominant-negative p53 mutants. In human esophageal keratinocytes, we found that Ha-Ras G12V induced senescence regardless of p53 status and telomerase activation. Ras activation resulted in changes of cellular morphology, activation of senescence-associated b-galactosidase, and suppression of cell proliferation, all coupled with reduction in the hyperphosphorylated form of the retinoblastoma protein (pRb). Furthermore, HaRas G12V upregulated p16 INK4a and downregulated cyclindependent kinase Cdk4 in human esophageal keratinocytes. Thus, Ras-mediated senescence may involve distinct mechanisms between human and mouse cells. Inactivation of the pRb pathway may be necessary for Ras to overcome senescence and transform human esophageal epithelial cells.

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“…p19 ARF has activities that do not depend on Mdm2 and p53. At least some of the p53-independent effects of p19 ARF might be mediated by its ability to inhibit ribosomal RNA processing (24) and transcriptional factors that induce proliferation such as E2F1 (25), Myc (26), and Foxm1b (27)(28)(29). The ability of NO to induce p53 accumulation has been largely studied; however, the molecular mechanisms underlying the induction of p53 by NO have not been fully elucidated and a direct connection between NO and p19 ARF has not been established.…”

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confidence: 99%

Specific Contribution of p19ARF to Nitric Oxide-Dependent Apoptosis

Zeini

Través

López-Fontal

et al. 2006

The Journal of Immunology

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NO is an important bioactive molecule involved in a variety of physio- and pathological processes, including apoptosis induction. The proapoptotic activity of NO involves the rise in the tumor suppressor p53 and the accumulation and targeting of proapoptotic members of the Bcl-2 family, in particular Bax and the release of cytochrome c from the mitochondria. However, the exact mechanism by which NO induces p53 activation has not been fully elucidated. In this study, we describe that NO induces p19ARF through a transcriptional mechanism. This up-regulation of p19ARF activates p53, leading to apoptosis. The importance of p19ARF on NO-dependent apoptosis was revealed by the finding that various cell types from alternate reading frame-knockout mice exhibit a diminished response to NO-mediated apoptosis when compared with normal mice. Moreover, the biological relevance of alternative reading frame to p53 apoptosis was confirmed in in vivo models of apoptosis. Together, these results demonstrate that NO-dependent apoptosis requires, in part, the activation of p19ARF.

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p19ARF-induced p53-independent apoptosis largely occurs through BAX

Cited by 16 publications

References 27 publications

Bak functionally complements for loss of Bax during p14ARF-induced mitochondrial apoptosis in human cancer cells

Bak functionally complements for loss of Bax during p14ARF-induced mitochondrial apoptosis in human cancer cells

Ha-RasG12V induces senescence in primary and immortalized human esophageal keratinocytes with p53 dysfunction

Specific Contribution of p19ARF to Nitric Oxide-Dependent Apoptosis

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