JNK Regulates the Release of Proapoptotic Mitochondrial Factors in Reovirus-Infected Cells

Clarke, Penny; Meintzer, Suzanne M.; Wang, Yibing; Moffitt, Lisa A.; Richardson-Burns, Sarah M.; Johnson, Gary L.; Tyler, Kenneth L.

doi:10.1128/jvi.78.23.13132-13138.2004

Cited by 59 publications

(71 citation statements)

References 44 publications

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“…Reolysin dramatically reduced cell viability in MM cell lines, while displaying much less potency against peripheral blood mononuclear cells (PBMCs) (Figure 1b). Reovirus infection has been reported to occur via oncolytic and apoptotic pathways, suggesting that it may kill cancer cells via multiple mechanisms (Clarke et al, 2004;Marcato et al, 2007). Expression profiling analysis of RNA isolated from U266 cells revealed that reovirus treatment induced a strong anti-viral response, which was characterized by interferon (IFN) stimulation (Supplementary Tables 1 and 2).…”

Section: Resultsmentioning

confidence: 99%

Reovirus therapy stimulates endoplasmic reticular stress, NOXA induction, and augments bortezomib-mediated apoptosis in multiple myeloma

et al. 2011

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Oncolytic virotherapy with reovirus has demonstrated anti-cancer activity and minimal toxicity in clinical trials, but the mechanisms underlying these effects have not been fully elucidated. Reolysin, a proprietary formulation of reovirus for cancer therapy, stimulated selective viral replication and apoptosis in multiple myeloma (MM) cells. Reolysin-mediated apoptosis was associated with an induction of endoplasmic reticular (ER) stress-related gene expression, swelling of the endoplasmic reticulum, increases in intracellular calcium levels and a strong induction of the Bcl-2 homology 3 (BH3)-only pro-apoptotic protein NOXA. Knockdown of NOXA expression by short hairpin RNA significantly reduced the pro-apoptotic effects of Reolysin. We next showed that co-administration of Reolysin and bortezomib resulted in the dual accumulation of viral and ubiquitinated proteins, which led to enhanced ER stress, NOXA induction and apoptosis. Importantly, the combination of reovirus infection and proteasomal inhibition significantly decreased tumor burden in a xenograft and syngeneic bone disease model of MM without exhibiting adverse side effects. Our study establishes ER stress stimulation and NOXA induction as novel mediators of reovirus-induced apoptosis. Furthermore, reovirus infection can be used as a promising approach to augment the anti-myeloma activity of bortezomib by promoting additional stress to the endoplasmic reticulum of MM cells.

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Section: Resultsmentioning

confidence: 99%

Reovirus therapy stimulates endoplasmic reticular stress, NOXA induction, and augments bortezomib-mediated apoptosis in multiple myeloma

et al. 2011

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“…These mechanisms include a signal transduction cascade involving mitogen-activated protein kinases such as c-Jun N-terminal protein kinase (JNK) and p38, as described for other models (21,49). The regulation of mitochondrial dysfunction by JNK following virus infection was first demonstrated with reovirus-infected cells (8). Holloway and Coulson (17) recently showed that JNK and p38 are activated by rotavirus infection in MA104 cells.…”

Section: Discussionmentioning

confidence: 99%

Bax Is Activated during Rotavirus-Induced Apoptosis through the Mitochondrial Pathway

Martin‐Latil

Mousson

Autret

et al. 2007

J Virol

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Rotaviruses are the leading cause of infantile viral gastroenteritis worldwide. Mature enterocytes of the small intestine infected by rotavirus undergo apoptosis, and their replacement by less differentiated dividing cells probably leads to defective absorptive function of the intestinal epithelium, which, in turn, contributes to osmotic diarrhea and rotavirus pathogenesis. Here we show that infection of MA104 cells by the simian rhesus rotavirus strain RRV induced caspase-3 activation, DNA fragmentation, and cleavage of poly(ADP-ribose) polymerase; all three phenomena are features of apoptosis. RRV induced the release of cytochrome c from mitochondria to the cytosol, indicating that the mitochondrial apoptotic pathway was activated. RRV infection of MA104 cells activated Bax, a proapoptotic member of the Bcl-2 family, as revealed by its conformational change. Most importantly, Bax-specific small interfering RNAs partially inhibited cytochrome c release in RRV-infected cells. Thus, mitochondrial dysfunction induced by rotavirus is Bax dependent. Apoptosis presumably leads to impaired intestinal functions, so our findings contribute to improving our understanding of rotavirus pathogenesis at the cellular level.

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“…There is also an increasing body of literature showing that JNK activation follows bacterial, fungal, prion, parasitic, or viral infections. Under these circumstances, JNK activation may influence important cellular consequences, such as alterations in gene expression (1,53,59,162,167,176,199,294,325,326,346), cell death (58,89,137,139,169,193,243,293), viral replication, persistent infection or progeny release (215,224,251,260), or altered cellular proliferation (178). The exact mechanism of JNK activation under each of these circumstances remains to be elucidated fully, although there may be involvement of Toll-like receptors, direct pathway modulation through interaction with upstream protein regulators, or the activation following an ER stress response (79,87,110,124,143,191,253,261,279,294,312).…”

Section: Fig 1 Overview Of the Jnk Pathway (A)mentioning

confidence: 99%

Uses for JNK: the Many and Varied Substrates of the c-Jun N-Terminal Kinases

Bogoyevitch

Kobe

2006

Microbiol Mol Biol Rev

530

477

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SUMMARY The c-Jun N-terminal kinases (JNKs) are members of a larger group of serine/threonine (Ser/Thr) protein kinases from the mitogen-activated protein kinase family. JNKs were originally identified as stress-activated protein kinases in the livers of cycloheximide-challenged rats. Their subsequent purification, cloning, and naming as JNKs have emphasized their ability to phosphorylate and activate the transcription factor c-Jun. Studies of c-Jun and related transcription factor substrates have provided clues about both the preferred substrate phosphorylation sequences and additional docking domains recognized by JNK. There are now more than 50 proteins shown to be substrates for JNK. These include a range of nuclear substrates, including transcription factors and nuclear hormone receptors, heterogeneous nuclear ribonucleoprotein K, and the Pol I-specific transcription factor TIF-IA, which regulates ribosome synthesis. Many nonnuclear substrates have also been characterized, and these are involved in protein degradation (e.g., the E3 ligase Itch), signal transduction (e.g., adaptor and scaffold proteins and protein kinases), apoptotic cell death (e.g., mitochondrial Bcl2 family members), and cell movement (e.g., paxillin, DCX, microtubule-associated proteins, the stathmin family member SCG10, and the intermediate filament protein keratin 8). The range of JNK actions in the cell is therefore likely to be complex. Further characterization of the substrates of JNK should provide clearer explanations of the intracellular actions of the JNKs and may allow new avenues for targeting the JNK pathways with therapeutic agents downstream of JNK itself.

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JNK Regulates the Release of Proapoptotic Mitochondrial Factors in Reovirus-Infected Cells

Cited by 59 publications

References 44 publications

Reovirus therapy stimulates endoplasmic reticular stress, NOXA induction, and augments bortezomib-mediated apoptosis in multiple myeloma

Reovirus therapy stimulates endoplasmic reticular stress, NOXA induction, and augments bortezomib-mediated apoptosis in multiple myeloma

Bax Is Activated during Rotavirus-Induced Apoptosis through the Mitochondrial Pathway

Uses for JNK: the Many and Varied Substrates of the c-Jun N-Terminal Kinases

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