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#33920735   2021/04/17 To Up

Atypical p38 Signaling, Activation, and Implications for Disease.

The mitogen-activated protein kinase (MAPK) p38 is an essential family of kinases, regulating responses to environmental stress and inflammation. There is an ever-increasing plethora of physiological and pathophysiological conditions attributed to p38 activity, ranging from cell division and embryonic development to the control of a multitude of diseases including retinal, cardiovascular, and neurodegenerative diseases, diabetes, and cancer. Despite the decades of intense investigation, a viable therapeutic approach to disrupt p38 signaling remains elusive. A growing body of evidence supports the pathological significance of an understudied atypical p38 signaling pathway. Atypical p38 signaling is driven by a direct interaction between the adaptor protein TAB1 and p38α, driving p38 autophosphorylation independent from the classical MKK3 and MKK6 pathways. Unlike the classical MKK3/6 signaling pathway, atypical signaling is selective for just p38α, and at present has only been characterized during pathophysiological stimulation. Recent studies have linked atypical signaling to dermal and vascular inflammation, myocardial ischemia, cancer metastasis, diabetes, complications during pregnancy, and bacterial and viral infections. Additional studies are required to fully understand how, when, where, and why atypical p38 signaling is induced. Furthermore, the development of selective TAB1-p38 inhibitors represents an exciting new opportunity to selectively inhibit pathological p38 signaling in a wide array of diseases.
Jeremy C Burton, William Antoniades, Jennifer Okalova, Morgan M Roos, Neil J Grimsey

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#33863779   2021/04/16 To Up

mTOR activation initiates renal cell carcinoma development by coordinating ERK and p38MAPK.

Renal cell carcinoma (RCC) mainly originates from renal proximal tubules. Intriguingly, disruption of genes frequently mutated in human RCC samples thus far has only generated RCC originated from other renal tubule parts in mouse models. This hampers our understanding of the pathogenesis of RCC. Here we show that mTOR signaling, often activated in RCC samples, initiates RCC development from renal proximal tubules. Ablation of Tsc1, encoding an mTOR suppressor, in proximal tubule cells led to multiple precancerous renal cysts. mTOR activation increased MEK1 expression and ERK activation, and Mek1 ablation or inhibition diminished cyst formation in Tsc1-deficient mice. mTOR activation also increased MKK6 expression and p38MAPK activation, and ablation of the p38α-encoding gene further enhanced cyst formation and led to RCC with clear cell RCC features. Mechanistically, Tsc1 deletion induced p53 and p16 expression in a p38MAPK-dependent manner, and deleting Tsc1 and Trp53 or Cdkn2a (encoding p16) enhanced renal cell carcinogenesis. Thus, mTOR activation in combination with inactivation of the p38MAPK-p53/p16 pathway drives RCC development from renal proximal tubules. Moreover, this study uncovers previously unidentified mechanisms by which mTOR controls cell proliferation and suggests the MEK-ERK axis to be a potential target for treatment of RCC.
Hongguang Wu, Dan He, Soma Biswas, Md Shafiquzzaman, Xin Zhou, Jean Charron, Yibin Wang, Bijaya K Nayak, Samy L Habib, Huijuan Liu, Baojie Li

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#33847130   2021/04/13 To Up

A novel antitumor peptide inhibits proliferation and migration and promotes apoptosis in glioma cells by regulating the MKK6/p38 signaling pathway.

Protein- or peptide-based therapeutics have emerged as an innovative strategy for the treatment of cancer. Our previous research demonstrated that tripartite motif 9 short isoform (TRIM9s) is a tumor suppressor in glioma. In this report, we investigated whether a new peptide derived from TRIM9s, named T9sP, inhibits glioma progression and determined the possible molecular mechanism. The CCK-8 proliferation assay was performed in LN229 and U251 glioma cells. The scratch-wound assay was used to determine the migration of the cells. Apoptosis was assessed by flow cytometry using Annexin V-FITC/PI double staining method. The relative protein expression levels were detected by immunoblot analysis. The cell-penetrating peptide TAT was fused with T9sP to form TAT-T9sP. TAT-T9sP efficiently penetrated through the cell membrane of both LN229 and U251 cells. TAT-T9sP inhibited proliferation and migration and promoted apoptosis of glioma cells. TAT-T9sP activated p38 signaling by upregulating MKK6, and a p38 inhibitor, SB203580, reversed the inhibitory effects of TAT-T9sP on glioma cells. These results indicated the potential of TAT-T9sP for the development of a new anti-glioma medicine.
Rong Wang, Bo-Wen Li, Nai-Yuan Shao, Dan-Ni Deng, Feng Zhi

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#33808629   2021/03/19 To Up

The PKR/P38/RIPK1 Signaling Pathway as a Therapeutic Target in Alzheimer's Disease.

Neuropathological lesions in Alzheimer's disease (AD) include amyloid plaques formed by the accumulation of amyloid peptides, neurofibrillary tangles made of hyperphosphorylated tau protein, synaptic and neuronal degenerations, and neuroinflammation. The cause of AD is unknown, but according to the amyloid hypothesis, amyloid oligomers could lead to the activation of kinases such as eukaryotic translation initiation factor 2-alpha kinase 2 (PKR), p38, and receptor-interacting serine/threonine-protein kinase 1 (RIPK1), which all belong to the same stress-activated pathway. Many toxic kinase activations have been described in AD patients and in experimental models. A p38 mitogen-activated protein kinase inhibitor was recently tested in clinical trials but with unsuccessful results. The complex PKR/P38/RIPK1 (PKR/dual specificity mitogen-activated protein kinase kinase 6 (MKK6)/P38/MAP kinase-activated protein kinase 2 (MK2)/RIPK1) is highly activated in AD brains and in the brains of AD transgenic animals. To delineate the implication of this pathway in AD, we carried out a search on PubMed including PKR/MKK6/p38/MK2/RIPK1, Alzheimer, and therapeutics. The involvement of this signaling pathway in the genesis of AD lesions, including Aβ accumulations and tau phosphorylation as well as cognitive decline, is demonstrated by the reports described in this review. A future combination strategy with kinase inhibitors should be envisaged to modulate the consequences for neurons and other brain cells linked to the abnormal activation of this pathway.
Jacques Hugon, Claire Paquet

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#33763149   2021/03/08 To Up

Electroacupuncture Pretreatment Regulates Apoptosis of Myocardial Ischemia-Reperfusion Injury in Rats Through RhoA/p38MAPK Pathway Mediated by miR-133a-5p.

The electroacupuncture (EA) pretreatment possesses a beneficial effect on myocardial ischemia/reperfusion (I/R) injury. However, the molecular mechanism of the EA effect is not fully understood. The study aimed to explore the protective effect of EA pretreatment on myocardial ischemia-reperfusion injury (MIRI) and apoptosis-related mechanisms in rats. Rats underwent in vivo myocardial ischemia-reperfusion, EA pretreatment, or intravenous injection of antagomirs. Cardiac function, infarct area, and myocardial cell apoptosis were measured. Meanwhile, the expressions of MKK3, MKK6, p38MAPK, Bax, Bcl-2, and Caspase-3 were also detected. We found that EA pretreatment significantly reduced infarct area and myocarpal cell apoptosis and enhanced cardiac function. EA pretreatment decreased the expression of Bax, Caspase-3, MKK3, MKK6, p38MAPK, Bax, and Caspase-3. In conclusion, The EA pretreatment down regulated the expression of MKK3, MKK6, and p38MAPK through the RhoA/p38MAPK pathway. EA pretreatment protect MIRI rats from apoptosis by down regulating the expression of MKK3, MKK6, and p38MAPK, thereby reducing the expression of Bax, Caspase-3 and up regulating the expression of Bcl-2, which mechanism is closely related to the RhoA/p38MAPK pathway mediated by miR-133a-5p.
Yongli Han, Song Chen, Hua Wang, Xing-Ming Peng

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#33554397   2021/02/16 To Up

The interaction of p38 with its upstream kinase MKK6.

Mitogen-activated protein kinase (MAPK; p38, ERK, and JNK) cascades are evolutionarily conserved signaling pathways that regulate the cellular response to a variety of extracellular stimuli, such as growth factors and interleukins. The MAPK p38 is activated by its specific upstream MAPK kinases, MKK6 and MKK3. However, a comprehensive molecular understanding of how these cognate upstream kinases bind and activate p38 is still missing. Here, we combine NMR spectroscopy and isothermal titration calorimetry to define the binding interface between full-length MKK6 and p38. It was shown that p38 engages MKK6 not only via its hydrophobic docking groove, but also influences helix αF, a secondary structural element that plays a key role in organizing the kinase core. It was also shown that, unlike MAPK phosphatases, the p38 conserved docking (CD) site is much less affected by MKK6 binding. Finally, it was demonstrated that these interactions with p38 are conserved independent of the MKK6 activation state. Together, the results revealed differences between specificity markers of p38 regulation by upstream kinases, which do not effectively engage the CD site, and downstream phosphatases, which require the CD site for productive binding.
Ganesan Senthil Kumar, Rebecca Page, Wolfgang Peti

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#33517263   // To Up

Acquisition of Letrozole Resistance Through Activation of the p38/MAPK Signaling Cascade.

Previous reports identified a global proteomic signature of estrogen-independent letrozole resistant breast cancer cells, however, it remains unclear how letrozole-resistance is impacted when cells remain estrogen receptor positive (ER+).
Rashidra R Walker, Karen M Gallegos, Melyssa R Bratton, Kitani P Lemieux, Kun Zhang, Guangdi Wang, A Michael Davidson, Syreeta L Tilghman

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#33483588   2021/01/22 To Up

BAFF, involved in B cell activation through the NF-κB pathway, is related to disease activity and bone destruction in rheumatoid arthritis.

B cell activating factor of TNF family (BAFF) is a member of TNF ligand superfamily and plays a key role in B cell homeostasis, proliferation, maturation, and survival. In this study, we detected BAFF level, the expressions of BAFF receptors and important molecules in NF-κB pathway in rheumatoid arthritis (RA) patients and analyzed the correlation between BAFF level and clinical variables, laboratory parameters or X-ray scores in order to elucidate the roles of BAFF in RA. A total of 50 RA patients and 50 healthy controls (HCs) were enrolled. We showed that the serum BAFF level in RA patients was significantly higher than that of HCs, and the percentages of B cell subsets (CD19 B cells, CD19CD27 B cells, CD19CD20CD27 B cells, and CD19CD20CD27 B cells) in the serum of RA patients were significantly increased compared with those of HCs. The percentages of CD19BAFFR B cells, CD19 BCMA B cells, and CD19 TACI B cells in RA patients were significantly increased compared with those in HCs. The expression of important molecules in the NF-κB pathway (MKK3, MKK6, p-P38, p-P65, TRAF2, and p52) was significantly higher in RA patients than in HCs, but p100 level in RA patients was lower than that in HCs. The serum BAFF level was positively correlated with C-reactive protein, rheumatoid factor, disease activity score (in 28 joints), swollen joint counts, tender joint counts, and X-ray scores. When normal B cells were treated with BAFF in vitro, the percentages of the B cell subset and the expression of BAFF receptors were significantly upregulated. BAFF also promoted the expression of MKK3, MKK6, p-P38, p-P65, TRAF2, and p52. In conclusion, this study demonstrates that BAFF level is correlated with the disease activity and bone destruction of RA. BAFF is involved in the differentiation, proliferation, and activation of B cells in RA through NF-κB signaling pathway, suggesting that BAFF might be an ideal therapeutic target for RA.
Ling-Ling Zhang, Hui Xiao, Feng Zhang, Yu-Jing Wu, Jin-Ling Shu, Ying Li, Yu Tai, Sheng-Qian Xu, Jian-Hua Xu, Wei Wei

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