Mixed – Lineage Protein kinases (MLKs) in inflammation, metabolism, and other disease states

Craige, Siobhan M.; Reif, Michaella M.; Kant, Shashi

doi:10.1016/j.bbadis.2016.05.022

Cited by 41 publications

(42 citation statements)

References 81 publications

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“…JNKs are specifically activated by two dual‐specificity MAP kinase kinases (MKKs), namely, MKK4 and MKK7, through phosphorylation of threonine and tyrosine . Similar to the activation of JNK, MKK4 and MKK7 are phosphorylated in their activation by upstream MAP kinase kinase kinases (MKKKs), including mixed lineage kinase (MLK)‐1‐4, DLK, TAK1, ASK1, LZK and ZAK . Recently, it was demonstrated that MLK3 silencing or MLK inhibition blocks JNK activation and both GBM cell migration and invasion, and silencing MLK4 suppresses self‐renewal, motility and radio‐resistance of glioma stem cells, suggesting that the MLK‐JNK axis is crucial for GBM tumourigenesis .…”

Section: Introductionmentioning

confidence: 99%

MKK7 transcription positively or negatively regulated by SP1 and KLF5 depends on HDAC4 activity in glioma

Wang

Xia

et al. 2019

Intl Journal of Cancer

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JNK activity has been implicated in the malignant proliferation, invasion and drug‐resistance of glioma cells (GCs), but the molecular mechanisms underlying JNK activation are currently unknown. Here, we reported that MKK7, not MKK4, directly activates JNK in GCs and exerts oncogenic effects on tumor formation. Notably, MKK7 expression in glioma tissues was closely correlated with the grade of the glioma and JNK/c‐Jun activation. Mechanistically, MKK7 transcription critically depends on the complexes formed by HDAC4 and the transcriptional factors SP1 and Krüppel‐like factor‐5 (KLF5), wherein HDAC4 directly deacetylates both SP1 and KLF5 and synergistically upregulates MKK7 transcription through two SP1 sites located on its promoter. In contrast, the increases in acetylated‐SP1 and acetylated‐KLF5 after HDAC4 inhibition switched to transcriptionally suppress MKK7. Selective inhibition of HDAC4 by LMK235, siRNAs or blockage of SP1 and KLF5 by the ectopic dominant‐negative SP1 greatly reduced the malignant capacity of GCs. Furthermore, suppression of both MKK7 expression and JNK/c‐Jun activities was involved in the tumor‐growth inhibitory effects induced by LMK235 in U87‐xenograft mice. Interestingly, HDAC4 is highly expressed in glioma tissues, and the rate of HDAC4 nuclear import is closely correlated with glioma grade, as well as with MKK7 expression. Collectively, these findings demonstrated that highly expressed MKK7 contributes to JNK/c‐Jun signaling‐mediated glioma formation. MKK7 transcription, regulated by SP1 and KLF5, critically depends on HDAC4 activity, and inhibition of HDAC4 presents a potential strategy for suppressing the oncogenic roles of MKK7/JNK/c‐Jun signaling in GCs.

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Section: Introductionmentioning

confidence: 99%

MKK7 transcription positively or negatively regulated by SP1 and KLF5 depends on HDAC4 activity in glioma

Wang

Xia

et al. 2019

Intl Journal of Cancer

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“…A set of sequentially-activated kinases comprise the core of the JNK signaling pathway, a developmentally regulated pathway that is also activated in response to stress signals [ 61 – 63 ]. JNK activity influences the establishment of planar polarity in the fly retina [ 64 ], but otherwise does not contribute significantly to eye development [ 65 ].…”

Section: Resultsmentioning

confidence: 99%

A screen for E3 ubiquitination ligases that genetically interact with the adaptor protein Cindr during Drosophila eye patterning

2017

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Ubiquitination is a crucial post-translational modification that can target proteins for degradation. The E3 ubiquitin ligases are responsible for recognizing substrate proteins for ubiquitination, hence providing specificity to the process of protein degradation. Here, we describe a genetic modifier screen that identified E3 ligases that modified the rough-eye phenotype generated by expression of cindrRNAi transgenes during Drosophila eye development. In total, we identified 36 E3 ligases, as well as 4 Cullins, that modified the mild cindrRNA mis-patterning phenotype. This indicates possible roles for these E3s/Cullins in processes that require Cindr function, including cytoskeletal regulation, cell adhesion, cell signaling and cell survival. Three E3 ligases identified in our screen had previously been linked to regulating JNK signaling.

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“…It located in the SH3 domain of MAP3K21, which was responsible for controlling or regulating protein-protein interactions in the signal transduction pathways, such as cytoplasmic signaling (Koch, Anderson, Moran, Ellis, & Pawson, 1991;Schlessinger, 1994). MAP3K21 is a member of the mixed lineage kinases family that acts as a specific modulator to inhibit lipopolysaccharide (LPS)-induced activation of c-Jun N-terminal kinase (JNK), or extracellular signal-regulated kinase (ERK) (Craige, Reif, & Kant, 2016), or as a negative regulator of Tolllike receptor 4 (TLR4) signaling (Seit-Nebi, Cheng, Xu, & Han, 2012). It's well known that JNK, ERK, and TLR4 are all implicated with obesity through elevating gene expression level (Ahmad et al, 2012;Hirosumi et al, 2002), promoting insulin resistance (Hirosumi et al, 2002;Ozaki et al, 2016;Pal et al, 2012;Solinas & Becattini, 2017), or stimulating adipogenic differentiation (Gu et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Coding Variants Affecting the Expression of Obesity-related Genes for Pediatric Adiposity

Mao¹,

Zhang²,

Cao³

et al. 2020

Preprint

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Objective Heredity has a remarkable effect on obesity in an obesogenic environment. Despite numerous genetic variants contributing to obesity-related traits, none of them was identified from Chinese children. We aim to identify novel variants and genes associated with childhood obesity in China. Methods We obtain promising single nucleotide variants from 76 obese and 74 normal weight children by whole-exome sequencing, and interrogate their associations with obesity traits in an additional 6,334 children cohort. We then depict the effects of genome-wide significant (P < 5E-8) variants on expression of implicated genes in blood and adipose tissues by transcriptome sequencing. Results We identify two coding variants associated with obesity at genome-wide significance: rs1059491 (P = 2.57E-28) in SULT1A2 and rs189326455 (P = 8.98E-12) in MAP3K21. In addition, rs1058491 is also significantly associated with several obesity traits. Transcriptome sequencing demonstrates that rs1059491 is an eQTL site associated with the expression levels of several obesity-related genes, such as SULT1A2, ATXN2L, and TUFM. Conclusions Our work identifies two coding variants affecting the expression of obesity-related genes based on a large Chinese pediatric adiposity cohort and provide new insights for the pathophysiology of Chinese childhood obesity.

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Mixed – Lineage Protein kinases (MLKs) in inflammation, metabolism, and other disease states

Cited by 41 publications

References 81 publications

MKK7 transcription positively or negatively regulated by SP1 and KLF5 depends on HDAC4 activity in glioma

MKK7 transcription positively or negatively regulated by SP1 and KLF5 depends on HDAC4 activity in glioma

A screen for E3 ubiquitination ligases that genetically interact with the adaptor protein Cindr during Drosophila eye patterning

Coding Variants Affecting the Expression of Obesity-related Genes for Pediatric Adiposity

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