A Time-Dependent Phase Shift in the Mammalian Unfolded Protein Response

Yoshida, Hiderou; Matsui, Toshie; Hosokawa, Nobuko; Kaufman, Randal J.; Nagata, Kazuhiro; Mori, Kazutoshi

doi:10.1016/s1534-5807(03)00022-4

Cited by 626 publications

(572 citation statements)

References 32 publications

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“…9,15 The ER stress response is generally characterized by a time-dependent refolding response, which is followed by a refolding and degradation response. 16 The latter response is mediated by the XBP1 transcription factor, and we investigated whether cisplatin induces splicing of the mRNA for this transcription factor, an event carried out by the IRE1 Rnase. 17 We found that 40 lM cisplatin did not induce XBP1 splicing in 224 melanoma cells at any time-point tested, whereas treatment with thapsigargin, an inhibitor of the endoplasmic reticulum Ca 21 pump, did induce splicing (Fig.…”

Section: Resultsmentioning

confidence: 99%

Acute apoptosis by cisplatin requires induction of reactive oxygen species but is not associated with damage to nuclear DNA

Berndtsson

Hägg

Panaretakis

et al. 2006

Intl Journal of Cancer

198

162

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Cisplatin is a broad-spectrum anticancer drug that is also widely used in experimental studies on DNA damage-induced apoptosis. Induction of apoptosis within 24-48 hr requires cisplatin concentrations that are at least one order of magnitude higher than the IC 50 . Here, we show that such high, apoptosis-inducing cisplatin concentrations induce cellular superoxide formation and that apoptosis is inhibited by superoxide scavengers. The same concentration limit and the requirement for superoxide are also true for induction of caspase activation in enucleated cells (cytoplasts), showing that cisplatin-induced apoptosis occurs independently of nuclear DNA damage. In contrast, lower cisplatin concentrations, which do not induce acute apoptosis, are sufficient for induction of DNA damage signaling. We propose that the antiproliferative effects of cisplatin at IC 50 doses involve premature senescence and secondary, nonstress-induced apoptosis. The higher doses currently used in in vitro studies lead to acute, stress-induced apoptosis that involves induction of superoxide but is largely DNA damage-independent. ' 2006 Wiley-Liss, Inc.Key words: cisplatin; DNA damage; apoptosis; senescence Cis-diamminedichloroplatinum (II) (cisplatin) is a commonly used anticancer agent, especially effective in the treatment of testicular carcinoma and also used to treat other malignancies such as ovarian, cervix, head-and-neck and small-cell lung cancer. 1 Cisplatin forms covalent bonds to the N7 positions of DNA purines to form intra-or interstrand crosslinks, and DNA is generally acknowledged as the primary target of cisplatin. 2,3 Cisplatin is a commonly used model agent for induction of DNA damage-dependent apoptosis in vitro. Acute apoptosis is induced within 24-36 hr, and major efforts have been performed to elucidate apoptotic signaling pathways induced by cisplatin within this time frame. These various studies have highlighted the roles of c-ABL, stressactivated protein kinases and p53 as downstream mediators of cisplatin-induced DNA damage and as mediators of apoptotic signaling (recently reviewed in 3 ). In addition to induction of apoptosis, cisplatin also induces premature senescence. 4 Premature senescence is currently thought to be related to replicative senescence, which has been demonstrated to be a DNA damage response. 5 During replicative senescence, signaling pathways involving ATM (Ataxia telangiectasia mutated) and p53 are activated by telomere uncapping. 5,6 The same signaling mechanisms are believed to be involved in premature senescence induced by DNA damaging drugs. 6,7 Apoptosis and senescence are obviously mutually exclusive cellular outcomes. The factors that decide whether cisplatin will trigger apoptosis or senescence are not clearly understood. In one scenario, senescence and apoptosis represent graded responses to increasing DNA damage. In more complex scenarios, cisplatin induces senescence and apoptosis by different (or partially different) mechanisms.As inducer of apoptosis, cisplatin is used at very d...

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Section: Resultsmentioning

confidence: 99%

Acute apoptosis by cisplatin requires induction of reactive oxygen species but is not associated with damage to nuclear DNA

Berndtsson

Hägg

Panaretakis

et al. 2006

Intl Journal of Cancer

198

162

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“…During ER stress, ATF6 is activated rapidly by proteolysis, which generally occurs before the activation of XBP-1s. This observation suggests that ATF6-dependent gene transcription precedes XBP-1-dependent gene transcription and may provide insight into the cellular response during prolonged ER stress (48). However, because XBP-1 can also bind to the ERSE element (39), considerable redundancy exists in ERSE-dependent gene expression.…”

Section: The Upr Maintains Cellular Homeostasis During Er Stressmentioning

confidence: 99%

The Unfolded Protein Response: A Novel Component of the Hypoxic Stress Response in Tumors

Feldman

Chauhan

Koong

2005

Molecular Cancer Research

279

222

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Hypoxia is a physiologically important endoplasmic reticulum (ER) stress that is present in all solid tumors. Numerous clinical studies have shown that tumor hypoxia predicts for decreased local control, increased distant metastases, and decreased overall survival in a variety of human tumors. Hypoxia selects for tumors with an increased malignant phenotype and increases the metastatic potential of tumor cells. Tumor cells respond to hypoxia and ER stress through the activation of the unfolded protein response (UPR). The UPR is an adaptive response to increase cell survival during ER stress. XBP-1 is a critical transcriptional regulator of this process and is required for tumor growth. Pancreatic ER kinase (PKR-like ER kinase) regulates the translational branch of the UPR and is also important in the growth of tumors. Although the exact mechanism has yet to be elucidated, recent data suggest that the UPR affects tumor growth through protection from apoptosis and may influence angiogenic signaling pathways. Targeting various components of the UPR is a promising therapeutic strategy. Understanding the relationship between hypoxia, the UPR, and tumor growth is crucial to improving current cancer therapies. (Mol Cancer Res 2005;3(11):597 -605)

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“…10 In a later phase, components of ER-associated degradation (ERAD), including ER degradation-enhancing a-mannosidase-like protein (EDEM), are transcriptionally induced to eliminate misfolded proteins in the ER by the ubiquitin-proteasome system. [11][12][13] The third involves activation of NFkB, a transcription factor known as a mediator of immune and antiapoptotic responses. 14 This pathway is designated ER overload response (EOR), because it is triggered by accumulation of membrane proteins in the ER.…”

mentioning

confidence: 99%

Roles of CHOP/GADD153 in endoplasmic reticulum stress

2003

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Endoplasmic reticulum (ER) is the site of synthesis and folding of secretory proteins. Perturbations of ER homeostasis affect protein folding and cause ER stress. ER can sense the stress and respond to it through translational attenuation, upregulation of the genes for ER chaperones and related proteins, and degradation of unfolded proteins by a quality-control system. However, when the ER function is severely impaired, the organelle elicits apoptotic signals. ER stress has been implicated in a variety of common diseases such as diabetes, ischemia and neurodegenerative disorders. One of the components of the ER stress-mediated apoptosis pathway is C/EBP homologous protein (CHOP), also known as growth arrestand DNA damage-inducible gene 153 (GADD153). Here, we summarize the current understanding of the roles of CHOP/ GADD153 in ER stress-mediated apoptosis and in diseases including diabetes, brain ischemia and neurodegenerative disease.

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A Time-Dependent Phase Shift in the Mammalian Unfolded Protein Response

Cited by 626 publications

References 32 publications

Acute apoptosis by cisplatin requires induction of reactive oxygen species but is not associated with damage to nuclear DNA

Acute apoptosis by cisplatin requires induction of reactive oxygen species but is not associated with damage to nuclear DNA

The Unfolded Protein Response: A Novel Component of the Hypoxic Stress Response in Tumors

Roles of CHOP/GADD153 in endoplasmic reticulum stress

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