The endoplasmic reticulum stress-inducible protein Niban regulates eIF2α and S6K1/4E-BP1 phosphorylation

Sun, Guo Dong; Kobayashi, Toshiyuki; Abe, Masaaki; Tada, Norio; Adachi, Hiroyuki; Shiota, Akira; Totsuka, Yoshikazu; Hino, Okio

doi:10.1016/j.bbrc.2007.06.021

Cited by 51 publications

(64 citation statements)

References 18 publications

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“…We noted that several of the novel Nrf2 targets are involved in translational control mechanisms; for example, EEF1A2 , EIF4E3, RND3 / RhoE (Table S1A) and FAM129A / Niban (Table S2A). EEF1A2 is a translation elongation factor gene that was previously shown to promote survival of mouse plasmacytoma cells [48], whereas EIF4E3 , RND3 / RhoE and FAM129A / Niban encode proteins that participate in various facets of cap-dependent translation initiation (described in more detail below) [38, 49, 50]. …”

Section: Resultsmentioning

confidence: 99%

“…FAM129A inhibits PERK-mediated phosphorylation of eIF2α [50]. Additionally, FAM129A and Rnd3 reciprocally modulate the activity of 4E-BP1, an inhibitor of eIF4E1 [49, 50]. Briefly, the dephosphorylated form of 4E-BP1 binds to eIF4E1, preventing binding of eIF4G and formation of the eIF4F complex.…”

Section: Resultsmentioning

confidence: 99%

“…mTORC1 phosphorylates 4E-BP1, leading to its dissociation from eIF4E1 which allows eIF4F formation and translation initiation [75]. FAM129A positively affects mTORC1 phosphorylation of 4E-BP1, thereby facilitating eIF4E1-driven translation [50]. In contrast, Rnd3 inhibits mTORC1 phosphorylation of 4E-BP1 which prevents 4E-BP1 disassociation from eIF4E1 and therefore inhibits eIF4E1 function [49].…”

Section: Resultsmentioning

confidence: 99%

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Noncanonical SQSTM1/p62-Nrf2 pathway activation mediates proteasome inhibitor resistance in multiple myeloma cells via redox, metabolic and translational reprogramming

et al. 2016

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Multiple Myeloma (MM) is a B-cell malignancy characterized by the accumulation of clonal plasma cells in the bone marrow, with drug resistance being a major cause of therapeutic failure. We established a carfilzomib-resistant derivative of the LP-1 MM cell line (LP-1/Cfz) and found that the transcription factor NF-E2 p45-related factor 2 (Nrf2; gene symbol NFE2L2) contributes to carfilzomib resistance. The mechanism of Nrf2 activation involved enhanced translation of Nrf2 as well as its positive regulator, the autophagy receptor sequestosome 1 (SQSTM1)/p62. The eukaryotic translation initiation factor gene EIF4E3 was among the Nrf2 target genes upregulated in LP-1/Cfz cells, suggesting existence of a positive feedback loop. In line with this, we found that siRNA knockdown of eIF4E3 decreased Nrf2 protein levels. On the other hand, elevated SQSTM1/p62 levels were due at least in part to activation of the PERK-eIF2α pathway. LP-1/Cfz cells had decreased levels of reactive oxygen species as well as elevated levels of fatty acid oxidation and prosurvival autophagy. Genetic and pharmacologic inhibition of the Nrf2-EIF4E3 axis or the PERK-eIF2α pathway, disruption of redox homeostasis or inhibition of fatty acid oxidation or autophagy conferred sensitivity to carfilzomib. Our findings were supported by clinical data where increased EIF4E3 expression was predictive of Nrf2 target gene upregulation in a subgroup of patients with chemoresistant minimal residual disease and relapsed/refractory MM. Thus, our data offer a preclinical rationale for including inhibitors of the SQSTM1/p62-Nrf2 pathway to the treatment regimens for certain advanced stage MM patients.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Noncanonical SQSTM1/p62-Nrf2 pathway activation mediates proteasome inhibitor resistance in multiple myeloma cells via redox, metabolic and translational reprogramming

et al. 2016

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“…6b). Niban is overexpressed in several cancers and modulate cell death through regulation of its expression and phosphorylation [62][63][64][65][66]. The antiapoptotic activity of Niban is governed by Akt-dependent phosphorylation as it disrupts p53-containing protein complex under UV-stress [28] and experimental overexpression of the protein alone failed to diminished apoptosis in tumor cells [67].…”

Section: Discussionmentioning

confidence: 99%

P2X7R antagonism after subfailure overstretch injury of blood vessels reverses vasomotor dysfunction and prevents apoptosis

Luo

Feldman

McCallister

et al. 2017

Purinergic Signalling

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Human saphenous vein (HSV) is harvested and prepared prior to implantation as an arterial bypass graft. Injury and the response to injury from surgical harvest and preparation trigger cascades of molecular events and contribute to graft remodeling and intimal hyperplasia. Apoptosis is an early response after implantation that contributes the development of neointimal lesions. Here, we showed that surgical harvest and preparation of HSV leads to vasomotor dysfunction, increased apoptosis and downregulation of the phosphorylation of the anti-apoptotic protein, Niban. A model of subfailure overstretch injury in rat aorta (RA) was used to demonstrate impaired vasomotor function, increased extracellular ATP (eATP) release, and increased apoptosis following pathological vascular injury. The subfailure overstretch injury was associated with activation of p38 MAPK stress pathway and decreases in the phosphorylation of the anti-apoptotic protein Niban. Treatment of RA after overstretch injury with antagonists to purinergic P2X7 receptor (P2X7R) antagonists or P2X7R/pannexin (PanX1) complex, but not PanX1 alone, restored vasomotor function. Inhibitors to P2X7R and PanX1 reduced stretch-induced eATP release. P2X7R/PanX1 antagonism led to decrease in p38 MAPK phosphorylation, restoration of Niban phosphorylation and increases in the phosphorylation of the anti-apoptotic protein Akt in RA and reduced TNFα-stimulated caspase 3/7 activity in cultured rat vascular smooth muscle cells. In conclusion, inhibition of P2X7R after overstretch injury restored vasomotor function and inhibited apoptosis. Treatment with P2X7R/PanX1 complex inhibitors after harvest and preparation injury of blood vessels used for bypass conduits may prevent the subsequent response to injury that lead to apoptosis and represents a novel therapeutic approach to prevent graft failure.

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“…Immunoprecipitation was performed using a monoclonal anti-HA agarose conjugate (Sigma, St Louis, MO, USA) according to the manufacturer's protocol. Then immunoblotting (IB) was performed as described earlier (Sun et al, 2007) using the appropriate antibodies against each tag (Sigma). In the case of GSM-tuberin, a transfection with a 1.5-fold greater amount of plasmid was also performed (lane GSMx1.5).…”

mentioning

confidence: 99%

The G1556S-type tuberin variant suppresses tumor formation in tuberous sclerosis 2 mutant (Eker) rats despite its deficiency in mTOR inhibition

et al. 2008

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Tuberin, a tumor-suppressor protein produced by the tuberous sclerosis gene TSC2, downregulates the RhebmTOR-S6K pathway (mTOR axis). Comparison of the effects of human tuberin mutations, such as G1556S, suggests that pathways other than the mTOR axis might also be involved in the pathogenesis of tuberous sclerosis. Here we test this possibility using the rat G1556S-type mutation (GSM) and a transgenic Eker (Tsc2 mutant) rat system. Cells expressing GSM-tuberin failed to downregulate the mTOR axis. GSM-tuberin had an altered localization, which underlie its reduced ability to form a complex with hamartin, and a site-specific alteration in phosphorylation status indicating diverse regulation by Akt. GSM-transgenic (GSM-Tg) rats exhibited suppression of macroscopic renal tumors following N-ethyl-Nnitrosourea treatment. Intriguingly, rats with weaker GSM-Tg expression showed microscopic cystic and pre-tumorous lesions that were restricted in size and expansion, although they had hyper-phosphorylation of ribosomal protein S6. These results highlight a novel pathway involving tuberin that regulates tumor suppression independently of the mTOR inhibitory function. Identification of such a novel pathway will provide clear implications for generation of new therapeutic targets in the treatment of these tumors.

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The endoplasmic reticulum stress-inducible protein Niban regulates eIF2α and S6K1/4E-BP1 phosphorylation

Cited by 51 publications

References 18 publications

Noncanonical SQSTM1/p62-Nrf2 pathway activation mediates proteasome inhibitor resistance in multiple myeloma cells via redox, metabolic and translational reprogramming

Noncanonical SQSTM1/p62-Nrf2 pathway activation mediates proteasome inhibitor resistance in multiple myeloma cells via redox, metabolic and translational reprogramming

P2X7R antagonism after subfailure overstretch injury of blood vessels reverses vasomotor dysfunction and prevents apoptosis

The G1556S-type tuberin variant suppresses tumor formation in tuberous sclerosis 2 mutant (Eker) rats despite its deficiency in mTOR inhibition

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