RACK1 antagonizes TNF-α-induced cell death by promoting p38 activation

Wang, Qingyang; Zhou, Silei; Wang, Jingyang; Cao, Jinglin; Zhang, Xueying; Wang, Jing; Han, Kun; Cheng, Qianqian; Qiu, Guang; Zhao, Yawei; Li, Xinying; Qiao, Chun‐Feng; Li, Yan; Hou, Chunmei; Zhang, Jiyan

doi:10.1038/srep14298

Cited by 9 publications

(13 citation statements)

References 26 publications

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“…On the other hand, RACK1 (Receptor for Activated C Kinase 1) modulates the activation of the p38 pathway by interacting directly with MKK3/6 and increasing their kinase activity without affecting their phosphorylation. The enhanced p38 activation mediated by RACK1 suppressed TNFα-induced cell death in L929 cells [ 45 ]. Intriguingly, this latter study further shows that the endogenous scaffolding interaction between MKK3/6 is increased upon stimulation by TNFα, which suggests that the phosphorylation of MKK3/6 is important for their interaction with RACK1.…”

Section: The P38 Pathwaysmentioning

confidence: 99%

“…Intriguingly, this latter study further shows that the endogenous scaffolding interaction between MKK3/6 is increased upon stimulation by TNFα, which suggests that the phosphorylation of MKK3/6 is important for their interaction with RACK1. In corollary, it is suggested that a yet unidentified conformational change results from MKK3/6 phosphorylation and leads to the subsequent binding to RACK1 [ 45 ]. Hence, it seems that RACK1 may act both as a scaffolding protein and as an allosteric modulator to underlie its interaction with MKK3/6.…”

Section: The P38 Pathwaysmentioning

confidence: 99%

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The p38 pathway, a major pleiotropic cascade that transduces stress and metastatic signals in endothelial cells

2017

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By gating the traffic of molecules and cells across the vessel wall, endothelial cells play a central role in regulating cardiovascular functions and systemic homeostasis and in modulating pathophysiological processes such as inflammation and immunity. Accordingly, the loss of endothelial cell integrity is associated with pathological disorders that include atherosclerosis and cancer. The p38 mitogen-activated protein kinase (MAPK) cascades are major signaling pathways that regulate several functions of endothelial cells in response to exogenous and endogenous stimuli including growth factors, stress and cytokines. The p38 MAPK family contains four isoforms p38α, p38β, p38γ and p38δ that are encoded by four different genes. They are all widely expressed although to different levels in almost all human tissues. p38α/MAPK14, that is ubiquitously expressed is the prototype member of the family and is referred here as p38. It regulates the production of inflammatory mediators, and controls cell proliferation, differentiation, migration and survival. Its activation in endothelial cells leads to actin remodeling, angiogenesis, DNA damage response and thereby has major impact on cardiovascular homeostasis, and on cancer progression. In this manuscript, we review the biology of p38 in regulating endothelial functions especially in response to oxidative stress and during the metastatic process.

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Section: The P38 Pathwaysmentioning

confidence: 99%

Section: The P38 Pathwaysmentioning

confidence: 99%

The p38 pathway, a major pleiotropic cascade that transduces stress and metastatic signals in endothelial cells

2017

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“…The interaction between RACK1 and various proteins in different cellular compartments plays a critical role in many physiological processes, such as cell motility, cell survival and death, proliferation, immune signaling, tumorigenesis and neuronal function. 5 , 6 , 7 , 8 , 9 , 10 Also, RACK1 can regulate global and specific translations in different ways. RACK1 is an integral component of ribosomal 40S subunit, 11 acts as a signaling platform for the translational machinery and regulates a late step in translation initiation.…”

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confidence: 99%

RACK1 depletion in the ribosome induces selective translation for non-canonical autophagy

et al. 2017

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RACK1, which was first demonstrated as a substrate of PKCβ II, functions as a scaffold protein and associates with the 40S small ribosomal subunit. According to previous reports, ribosomal RACK1 was also suggested to control translation depending on the status in translating ribosome. We here show that RACK1 knockdown induces autophagy independent of upstream canonical factors such as Beclin1, Atg7 and Atg5/12 conjugates. We further report that RACK1 knockdown induces the association of mRNAs of LC3 and Bcl-xL with polysomes, indicating increased translation of these proteins. Therefore, we propose that the RACK1 depletion-induced autophagy is distinct from canonical autophagy. Finally, we confirm that cells expressing mutant RACK1 (RACK1R36D/K38E) defective in ribosome binding showed the same result as RACK1-knockdown cells. Altogether, our data clearly show that the depletion of ribosomal RACK1 alters the capacity of the ribosome to translate specific mRNAs, resulting in selective translation of mRNAs of genes for non-canonical autophagy induction.

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“…It can interact with multiple signaling molecules, including Akt, Bcl-2 ( 35 ), MCM7 ( 36 ), FGFR1 and PKM2 ( 37 ). Wang et al found that RACK1 antagonized TNF-α-induced cell death by promoting p38 activation ( 38 ). Li et al found that RACK1 was upregulated in proliferating pancreatic ductal adenocarcinoma (PDAC) cells, and involved in regulating cell cycle and apoptosis of PDAC cells by interact with cyclin D1, BCL-2 and caspase-3 ( 15 ).…”

Section: Discussionmentioning

confidence: 99%

The receptor for activated protein kinase C promotes cell growth, invasion and migration in cervical cancer

Liao

Xiao

Chen

et al. 2017

International Journal of Oncology

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Cervical cancer is one of the most common malignant tumors in women all over the world. However, the exact etiology of cervical cancer remains unclear. The receptor for activated protein kinase C (RACK1) is reported to be involved in tumorigenesis and tumor progression. Besides, the prognostic value of RACK1 in several kinds of tumors has been identified. However, there are limited studies on the functional role of RACK1 in cervical cancer. In this study, we tested the expression level of RACK1 by immunohistochemistry and western blot technologies and find that it is upregulated in cervical cancer. Colony formation and CCK8 assays indicate that RACK1 promotes cell proliferation in CaSki cervical cancer cells. While the silence of RACK1 decreases the cell proliferation in CCK8 analysis. β-galactosidase staining suggests that RACK1 decreases cell senescence in cervical cancer cells. Invasion and migration assay show that RACK1 promotes the invasion and migration of cervical cancer cells. Also, when RACK1 was silenced, it exerts the opposite result. Furthermore, the mRNA expression levels of MMP-3, MMP-9 and MMP-10 were upregulated in RACK1-overexpressed CaSki cells by qPCR analysis. RACK1 also induces S phase accumulation in cell cycle analysis and suppresses cell apoptosis in cervical cancer cells. Flow cytometry analysis of mitochondria functions suggests that RACK1 increases the mitochondrial membrane potential (Δψm) levels to prevent mitochondrial apoptosis in cervical cancer cells. To explore the possible mechanism of RACK1, we tested and found that RACK1 upregulates the expression of NF-κB, cyclin D1 and CDK4 and downregulates the expression of p53, p38, p21 and STAT1 in cervical cancer cells. These results suggest that RACK1 promotes cell growth and invasion and inhibits the senescence and apoptosis in cervical cancer cells probably by affecting the p53 pathway.

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RACK1 antagonizes TNF-α-induced cell death by promoting p38 activation

Cited by 9 publications

References 26 publications

The p38 pathway, a major pleiotropic cascade that transduces stress and metastatic signals in endothelial cells

The p38 pathway, a major pleiotropic cascade that transduces stress and metastatic signals in endothelial cells

RACK1 depletion in the ribosome induces selective translation for non-canonical autophagy

The receptor for activated protein kinase C promotes cell growth, invasion and migration in cervical cancer

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