Survival function of ERK1/2 as IL-3-activated, staurosporine-resistant Bcl2 kinases

Deng, Xingming; Ruvolo, Peter P.; Carr, Boyd; May, W. Stratford

doi:10.1073/pnas.97.4.1578

Cited by 226 publications

(253 citation statements)

References 47 publications

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“…Mcl-1 and Bcl-2 are two antiapoptotic proteins that are targets for MAPKs in some cells. 24,25 In osteosarcoma cells, we found that atorvastatin decreased Mcl-1 and Bcl-2 levels (Figure 6c). Interestingly, atorvastatin had no effect on the proapoptotic protein Bax (Figure 6c) or on Bcl-xl, Bid or Bim, which are other modulators of apoptosis (data not shown).…”

Section: Statin-induced Osteosarcoma Cell Apoptosis Involves Ggppmentioning

confidence: 85%

“…Our finding that restoration of RhoA activity abolished the inhibition of Bcl-2 and prevented cell death induced by statins indicates that Bcl-2 plays an essential role in protecting osteosarcoma cells from apoptosis induced by RhoA inactivation. Although a link between MAPKs, Bcl-2 and Mcl-1 has been reported in some other cell types, 24,25 and RhoA inhibition has been linked to Bcl-2 downregulation in the induction of apoptosis by statins in some cancer cells, 28,34,38 evidence implicating these molecules in the mechanisms of action of statins in human osteosarcoma cells was lacking. The present results point to a direct implication of p42/p44-MAPKs signaling downstream of RhoA as a mediator of the effects of statins on Bcl-2 and apoptosis in osteosarcoma cells.…”

Section: Discussionmentioning

confidence: 99%

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RhoA GTPase inactivation by statins induces osteosarcoma cell apoptosis by inhibiting p42/p44-MAPKs-Bcl-2 signaling independently of BMP-2 and cell differentiation

et al. 2006

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Osteosarcoma is the most common primary bone tumour in young adults. Despite improved prognosis, resistance to chemotherapy remains responsible for failure of osteosarcoma treatment. The identification of signals that promote apoptosis may provide clues to develop new therapeutic strategies for chemoresistant osteosarcoma. Here, we show that lipophilic statins (atorvastatin, simvastatin, cerivastatin) markedly induce caspases-dependent apoptosis in various human osteosarcoma cells, independently of bone morphogenetic protein (BMP)-2 signaling and cell differentiation. Although statins increased BMP-2 expression, the proapoptotic effect of statins was not prevented by the BMP antagonist noggin, and was abolished by mevalonate and geranylgeranylpyrophosphate, suggesting the involvement of defective protein geranylgeranylation. Consistently, lipophilic statins induced membrane RhoA relocalization to the cytosol and inhibited RhoA activity, which resulted in decreased phospho-p42/p44-mitogen-activated protein kinases (MAPKs) and Bcl-2 levels. Constitutively active RhoA rescued phospho-p42/p44-MAPKs and Bcl-2 and abolished statininduced apoptosis. Thus, lipophilic statins induce caspasedependent osteosarcoma cell apoptosis by a RhoA-p42/p44 MAPKs-Bcl-2-mediated mechanism, independently of BMP-2 signaling and cell differentiation.

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Section: Statin-induced Osteosarcoma Cell Apoptosis Involves Ggppmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

RhoA GTPase inactivation by statins induces osteosarcoma cell apoptosis by inhibiting p42/p44-MAPKs-Bcl-2 signaling independently of BMP-2 and cell differentiation

et al. 2006

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“…The notion that AA causes translocation 35 and activation of protein kinase C, 36 as well as stimulation of extracellular signal-regulated kinases 1/2 phosphorylation, 37 is well established and these events were shown to prevent apoptosis. 38,39 Thus, the question to be answered is whether these pathways also mediate the protective effects of AA in the peroxynitrite-dependent necrotic response.…”

Section: Discussionmentioning

confidence: 99%

Hydrogen peroxide generated at the level of mitochondria in response to peroxynitrite promotes U937 cell death via inhibition of the cytoprotective signalling mediated by cytosolic phospholipase A2

et al. 2004

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We have studied the relationships existing between delayed formation of H 2 O 2 and activation of cytosolic phospholipase A 2 (cPLA 2 ), events respectively promoting toxicity or survival in U937 cells exposed to peroxynitrite. The outcome of an array of different approaches using phospholipase A 2 inhibitors, or cPLA 2 antisense oligonucleotides, as well as specific respiratory chain inhibitors and respiration-deficient cells led to the demonstration that H 2 O 2 does not mediate toxicity by producing direct molecular damage. Rather, the effects of H 2 O 2 were found to be upstream to the arachidonic acid (AA)-mediated cytoprotective signalling and in fact causally linked to inhibition of cPLA 2 . Thus, it appears that U937 cells exposed to nontoxic concentrations of peroxynitrite are nevertheless committed to death, which however is normally prevented by the activation of parallel pathways resulting in cPLA 2 -dependent release of AA. A rapid necrotic response, however, takes place when high concentrations of peroxynitrite promote formation of H 2 O 2 at levels impairing the cPLA 2 cytoprotective signalling.

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“…To further uncover the mechanism by which Ku70 regulates the stability of Mcl-1, localization of Ku70 and Mcl-1 was analyzed by subcellular fractionation as we described in 'Materials and Methods'. [30][31][32] As shown in Figure 5a, left panel, Ku70 was colocalized with Mcl-1 in heavy membrane (HM) containing mitochondria, In addition, radiation also slightly enhanced Ku70 levels in the mitochondria (that is, from 19 to 22%) or ER (that is, from 18 to 20%) (Figure 5a). To verify the purity of the subcellular fractions obtained, fraction-specific proteins were assessed by probing the same filters.…”

Section: Ku70 Partially Colocalizes and Directly Interacts Withmentioning

confidence: 84%

Role of Ku70 in deubiquitination of Mcl-1 and suppression of apoptosis

Wang

Xie

et al. 2014

Cell Death Differ

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Mcl-1 is a unique antiapoptotic Bcl2 family member with a short half-life due to its rapid turnover through ubiquitination. We discovered that Ku70, a DNA double-strand break repair protein, functions as a deubiquitinase to stabilize Mcl-1. Ku70 knockout in mouse embryonic fibroblast (MEF) Mcl-1 is an antiapoptotic molecule that is overexpressed in various types of cancers, including lung cancer, 1 leukemia, 2 lymphoma, 3 hepatocellular carcinoma 4 and so on. In addition to its antiapoptotic function, Mcl-1 is also an oncoprotein that promotes the development of cancer. 5 In contrast to other Bcl2 family members such as Bcl2 and Bcl-XL, Mcl-1 is unique in its short half-life (30 min-3 h) and short-term prosurvival function, which probably relates to the presence of a long proline-, glutamic acid-, serine-and threonine-rich (PEST) region upstream of the Bcl2 homology (BH) domain. 1 The mechanism(s) that stabilizes the Mcl-1 protein are critical for its long-term survival function. Mcl-1 protein can be phosphorylated at multiple sites that distinctly regulate Mcl-1 protein turnover. For example, extracellular signal-regulated kinase 1/2-mediated T163 site phosphorylation enhances the half-life and antiapoptotic function of Mcl-1. 1,6 In contrast, S159 phosphorylation by GSK-3b facilitates Mcl-1 ubiquitination and degradation to reduce its survival activity. 7 Ubiquitination and deubiquitination are two reversible processes that can control protein stability. E3 ligases and deubiquitinases (deubiquitinating enzymes (DUBs)) are two groups of regulatory enzymes that orchestrate the ubiquitination levels of target proteins in eukaryotic cells. 8 Recently, Mule and FBW7 have been identified as Mcl-1 ubiquitin E3 ligases that can directly induce polyubiquitination and degradation of Mcl-1. 9,10 Inversely, USP9X has been demonstrated as the Mcl-1 deubiquitinase that removes the Lys 48-linked polyubiquitin chains that normally mark Mcl-1 for proteasomal degradation, leading to stabilization of Mcl-1. 3 Therefore, the stability of Mcl-1 in cells is tightly regulated by its E3 ligases and deubiquitinase, which is dependent on Mcl-1 phosphorylation status. 3,11 Ku70 is a protein that binds to DNA double-strand break (DSB) ends and is required for the non-homologous endjoining pathway of DSB repair. 12-15 The Ku70 protein consists of three structural domains, including the N-terminal, central (that is, DNA binding) and C-terminal domains. 16,17 Ku70 usually heterodimerizes with Ku86, which forms a functional complex for DSB repair. By forming a bridge between the broken DNA ends, the Ku70/Ku86 heterodimer acts to structurally support and align the DNA ends, to protect them from degradation and to prevent promiscuous binding to unbroken DNA. Ku70/Ku86 effectively aligns the DNA, while still allowing access of polymerases, nucleases and ligases to the broken DNA ends to promote end joining. 18 In some cases, a fourth domain is present at the C terminus of Ku86, which binds to the DNA-dependent protein kinase catalytic subunit...

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Survival function of ERK1/2 as IL-3-activated, staurosporine-resistant Bcl2 kinases

Cited by 226 publications

References 47 publications

RhoA GTPase inactivation by statins induces osteosarcoma cell apoptosis by inhibiting p42/p44-MAPKs-Bcl-2 signaling independently of BMP-2 and cell differentiation

RhoA GTPase inactivation by statins induces osteosarcoma cell apoptosis by inhibiting p42/p44-MAPKs-Bcl-2 signaling independently of BMP-2 and cell differentiation

Hydrogen peroxide generated at the level of mitochondria in response to peroxynitrite promotes U937 cell death via inhibition of the cytoprotective signalling mediated by cytosolic phospholipase A2

Role of Ku70 in deubiquitination of Mcl-1 and suppression of apoptosis

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