Activation of Rac GTPase by p75 Is Necessary for c-<i>jun</i>N-Terminal Kinase-Mediated Apoptosis

Harrington, Anthony; Kim, Ju Young; Yoon, Sung Ok

doi:10.1523/jneurosci.22-01-00156.2002

Cited by 188 publications

(185 citation statements)

References 63 publications

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“…Rho GTPases have a role in a number of cellular processes such as cytoskeleton remodeling, transcriptional activation, growth control, metastasis, development, and apoptosis. In particular, several groups have indicated Rac as either positive or negative player in the apoptotic program, depending on the cell line investigated and on the stimulus applied (Nishida et al, 1999;Embade et al, 2000;Deshpande et al, 2000;Pervaiz et al, 2001;Harrington et al, 2002;Murga et al, 2002;Zhang et al, 2004). However, the majority of the reports ascribe a protective role to active Rac1.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic Necrotizing Factor 1 Prevents Apoptosis via the Akt/IκB Kinase Pathway: Role of Nuclear Factor-κB and Bcl-2

Miraglia

Travaglione²,

Meschini

et al. 2007

MBoC

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Cytotoxic necrotizing factor 1 (CNF1) is a protein toxin produced by some pathogenic strains of Escherichia coli that specifically activates Rho, Rac, and Cdc42 GTPases. We previously reported that this toxin prevents the ultraviolet-Binduced apoptosis in epithelial cells, with a mechanism that remained to be defined. In this work, we show that the proteasomal degradation of the Rho GTPase is necessary to achieve cell death protection, because inhibition of Rho degradation abolishes the prosurvival activity of CNF1. We hypothesize that Rho inactivation allows the activity of Rac to become dominant. This in turn leads to stimulation of the phosphoinositide 3-kinase/Akt/I B kinase/nuclear factor-B prosurvival pathway and to a remarkable modification in the architecture of the mitochondrial network, mainly consisting in the appearance of elongated and interconnected mitochondria. Importantly, we found that Bcl-2 silencing reduces the ability of CNF1 to protect cells against apoptosis and that it also prevents the CNF1-induced mitochondrial changes. It is worth noting that the ability of a bacterial toxin to induce such a remodeling of the mitochondrial network is herein reported for the first time. The possible pathophysiological relevance of this finding is discussed. INTRODUCTIONToday, it is largely acknowledged that apoptosis, besides being an evolutionary conserved form of cell death that plays a pivotal role during development, morphogenesis, and cell homeostasis, is also critically implied in a constantly growing number of diseases (Fadeel and Orrenius, 2005). In fact, apoptosis can be regarded as a widespread strategy exploited by pathogenic bacteria to favor their own survival or spreading in the host , often by producing protein toxins that mediate their long-range cross-talk with host cells. In this context, we have previously reported the ability of a protein toxin from Escherichia coli, namely the cytotoxic necrotizing factor 1 (CNF1), to prevent the ultraviolet-B (UVB)-induced apoptosis and to increase the expression of antiapoptotic Bcl-2 family proteins (Fiorentini et al., 1998). The precise mechanism by which CNF1 allows cells to survive, however, is not yet defined.CNF1 is a protein toxin produced by some pathogenic strains of E. coli mainly involved in extraintestinal infections (Landraud et al., 2000). In eukaryotic cells, CNF1 binds to its receptor, reported to be the receptor of laminin , and it is endocytosed and released into the cytoplasm by an acidic-dependent mechanism (Contamin et al., 2000). Once in the cytoplasm, CNF1 exerts its enzymatic activity that is represented by deamidation of a pivotal glutamine residue of the guanosine triphosphate (GTP)-binding proteins Rho, Rac, and Cdc42 (glutamine 63 of Rho or glutamine 61 of Rac and Cdc42), giving rise to a glutamic acid (Flatau et al., 1997;Schmidt et al., 1997;Lerm et al., 1999). The glutamine residue modified by CNF1 lies in the switch 2 domain of Rho proteins, which is involved in GTP hydrolysis; thus, the modification exerted by CNF1...

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Section: Discussionmentioning

confidence: 99%

Cytotoxic Necrotizing Factor 1 Prevents Apoptosis via the Akt/IκB Kinase Pathway: Role of Nuclear Factor-κB and Bcl-2

Miraglia

Travaglione²,

Meschini

et al. 2007

MBoC

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“…RacGTP Assays and Western Blotting-RacGTP assays were performed as described (14). For quantification, RacGTP signals were adjusted to total Rac1 to obtain "relative RacGTP levels."…”

Section: Methodsmentioning

confidence: 99%

“…For quantification, RacGTP signals were adjusted to total Rac1 to obtain "relative RacGTP levels." The lysates were prepared and processed as described (14).…”

Section: Methodsmentioning

confidence: 99%

Brain-derived Neurotrophic Factor (BDNF) Induces Polarized Signaling of Small GTPase (Rac1) Protein at the Onset of Schwann Cell Myelination through Partitioning-defective 3 (Par3) Protein

Tep

Kim

Opincariu

et al. 2012

Journal of Biological Chemistry

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Background: Both p75 and Par3 become localized in a polarized manner in Schwann cells. Results: BDNF activates Rac1 at the axon-glial interface, regulated by Par3, thereby facilitating proper alignment between the axon and Schwann cells. Conclusion: Polarized localization of Rac1 activation is critical for myelination. Significance: Par3 is involved in Rac1 activation by BDNF-p75 at the axon-glial interface, thereby promoting myelination.

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“…67 Ad-GFP (GFP: green fluorescence protein) and Ad-dnJNK2 (encoding an HA-tagged dominant-negative JNK2 mutant) Ads 68 and the Flag-MKP6-expressing retroviral vector have been described before. 35 …”

Section: Adenovirus and Retrovirusesmentioning

confidence: 99%

ZBP-89-induced apoptosis is p53-independent and requires JNK

et al. 2004

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ZBP-89 induces apoptosis in human gastrointestinal cancer cells through a p53-independent mechanism. To understand the apoptotic pathway regulated by ZBP-89, we identified downstream signal transduction targets. Ectopic expression of ZBP-89 induced apoptosis through the mitochondrial pathway and was accompanied by activation of all three MAP kinase subfamilies: JNK1/2, ERK1/2 and p38 MAP kinase. ZBP-89-induced apoptosis was markedly enhanced by ERK inhibition with U0126. In contrast, inhibiting JNK with a JNK1-specific peptide inhibitor or dominant-negative JNK2 expression abrogated ZBP-89-mediated apoptosis. The p38 inhibitor SB202190 had no effect on ZBP-89-induced cell death. Protein dephosphorylation assays revealed that ZBP-89 activates JNK via repression of JNK dephosphorylation. Oligonucleotide microarray analyses revealed that ectopic expression of ZBP-89 downregulated expression of the dual-specificity phosphatase MKP6. Overexpression of MKP6 blocked ZBP-89-induced JNK phosphorylation and PARP cleavage. In addition, ectopic expression of ZBP-89 repressed Bcl-xL and Mcl-1 expression, but had no effect on Bcl-2. Silencing ZBP-89 with small interfering RNA enhanced both Bcl-xL and Mcl-1 expression. Taken together, ZBP-89-mediated apoptosis occurs via a p53-independent mechanism that requires JNK activation.

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Activation of Rac GTPase by p75 Is Necessary for c-junN-Terminal Kinase-Mediated Apoptosis

Cited by 188 publications

References 63 publications

Cytotoxic Necrotizing Factor 1 Prevents Apoptosis via the Akt/IκB Kinase Pathway: Role of Nuclear Factor-κB and Bcl-2

Cytotoxic Necrotizing Factor 1 Prevents Apoptosis via the Akt/IκB Kinase Pathway: Role of Nuclear Factor-κB and Bcl-2

Brain-derived Neurotrophic Factor (BDNF) Induces Polarized Signaling of Small GTPase (Rac1) Protein at the Onset of Schwann Cell Myelination through Partitioning-defective 3 (Par3) Protein

ZBP-89-induced apoptosis is p53-independent and requires JNK

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