<i>mda-5</i>: An interferon-inducible putative RNA helicase with double-stranded RNA-dependent ATPase activity and melanoma growth-suppressive properties

Kang, Dong Chul; Gopalkrishnan, Rahul V.; Wu, Qingping; Jankowsky, Eckhard; Pyle, Anna Marie; Fisher, Paul B.

doi:10.1073/pnas.022637199

Cited by 588 publications

(506 citation statements)

References 30 publications

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“…79,80 Melanoma differentiation-associated gene 5 (Mda5) (also known as Helicard) is structurally similar to RIG-I, which also contains two CARD-like and a single helicase domain, and is suggested to mediate antiviral responses (Figure 4). [81][82][83][84] LGP2 is also related to RIG-I and Mda5, but lacks the CARDlike domains, and is therefore suggested to function as a negative regulator for RIG-I and Mda5 (Figure 4). 84 …”

Section: Recognition Of Viral Components By Non-tlr Sensorsmentioning

confidence: 99%

TLR signaling

2006

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The Toll-like receptor (TLR) family plays an instructive role in innate immune responses against microbial pathogens, as well as the subsequent induction of adaptive immune responses. TLRs recognize specific molecular patterns found in a broad range of microbial pathogens such as bacteria and viruses, triggering inflammatory and antiviral responses and dendritic cell maturation, which result in the eradication of invading pathogens. Individual TLRs interact with different combinations of adapter proteins and activate various transcription factors such as nuclear factor (NF)-jB, activating protein-1 and interferon regulatory factors, driving a specific immune response. This review outlines the recent advances in our understanding of TLR-signaling pathways and their roles in immune responses. Further, we also discuss a new concept of TLR-independent mechanisms for recognition of microbial pathogens.

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Section: Recognition Of Viral Components By Non-tlr Sensorsmentioning

confidence: 99%

TLR signaling

2006

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“…Retinoic acid inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) are RNA helicase-containing cytoplasmic proteins. The RNA helicase domains of RIG-I and MDA5 bind directly to double-stranded RNA (dsRNA) and induce production of type I interferons (Kang et al, 2002;Andrejeva et al, 2004;Yoneyama et al, 2004). Upon binding to dsRNA, representing either the viral genome or viral replication intermediate, RIG-I and MDA5 induce the activation of IRF3 and NF-kB.…”

Section: Retinoic Acid Inducible Gene I and Melanoma Differentiation-mentioning

confidence: 99%

NF-κB and the immune response

2006

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Section: Introductionmentioning

confidence: 99%

“…[1][2][3] Melanoma differentiation-associated gene-5 (mda-5) was initially identified by subtraction hybridization as an upregulated transcript in terminally differentiated HO-1 human melanoma cells. 3,4 The encoded MDA-5 protein was recognized as the first molecule with a unique structural combination: an N-terminal caspase recruitment domain (CARD) and a C-terminal putative RNA helicase domain. 3,4 Our previous studies demonstrate that mda-5 is an early interferon inducible gene, and its expression requires an intact interferon signaling pathway, as there is no detectable expression of mda-5 in cells containing defects in the Jak/Stat signaling pathway upon interferon treatment.…”

Section: Introductionmentioning

confidence: 99%

“…3,4 The encoded MDA-5 protein was recognized as the first molecule with a unique structural combination: an N-terminal caspase recruitment domain (CARD) and a C-terminal putative RNA helicase domain. 3,4 Our previous studies demonstrate that mda-5 is an early interferon inducible gene, and its expression requires an intact interferon signaling pathway, as there is no detectable expression of mda-5 in cells containing defects in the Jak/Stat signaling pathway upon interferon treatment. 4 Based on the presence in the MDA-5 protein of a CARD motif, a proapoptotic element present in many caspases that facilitates cell death through homophilic protein-protein interactions, we proposed that mda-5 might play a role in mediating programmed cell death.…”

Section: Introductionmentioning

confidence: 99%

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Activation of Ras/Raf protects cells from melanoma differentiation-associated gene-5-induced apoptosis

Lin

Lebedeva

et al. 2006

Cell Death Differ

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Melanoma differentiation-associated gene-5 (mda-5) was the first molecule identified in nature whose encoded protein embodied the unique structural combination of an N-terminal caspase recruitment domain and a C-terminal DExD/H RNA helicase domain. As suggested by its structure, cumulative evidences documented that ectopic expression of mda-5 leads to growth inhibition and/or apoptosis in various cell lines. However, the signaling pathways involved in mda-5-mediated killing have not been elucidated. In this study, we utilized either genetically modified cloned rat embryo fibroblast cells overexpressing different functionally and structurally distinct oncogenes or human pancreatic and colorectal carcinoma cells containing mutant active ras to resolve the role of the Ras/Raf signaling pathway in mda-5-mediated growth inhibition/apoptosis induction. Rodent and human tumor cells containing constitutively activated Raf/Raf/MEK/ERK pathways were resistant to mda-5-induced killing and this protection was antagonized by intervening in this signal transduction cascade either by directly inhibiting ras activity using an antisense strategy or by targeting ras-downstream factors, such as MEK1/2, with the pharmacological inhibitor PD98059. The present findings provide a further example of potential cross-talk between growth-inhibitory and growth-promoting pathways in which the ultimate balance of these factors defines cellular homeostasis, leading to survival or induction of programmed cell death.

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mda-5: An interferon-inducible putative RNA helicase with double-stranded RNA-dependent ATPase activity and melanoma growth-suppressive properties

Cited by 588 publications

References 30 publications

TLR signaling

TLR signaling

NF-κB and the immune response

Activation of Ras/Raf protects cells from melanoma differentiation-associated gene-5-induced apoptosis

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