Initiation factor eIF3 and regulation of mRNA translation, cell growth, and cancer

Dong, Zizheng; Zhang, Jian-Ting

doi:10.1016/j.critrevonc.2006.03.005

Cited by 130 publications

(121 citation statements)

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“…There is prior evidence that p170/ eIF3A is overexpressed in certain malignancies and may be involved in the regulation of cell cycle progression and proliferation (6,11). Notably, inhibiting p170/eIF3A expression has been associated with arrest of the growth of lung and breast carcinoma cells (12).…”

Section: Discussionmentioning

confidence: 99%

Interferon-Dependent Engagement of Eukaryotic Initiation Factor 4B via S6 Kinase (S6K)- and Ribosomal Protein S6K-Mediated Signals

Kroczyńska

Kaur

Katsoulidis

et al. 2009

Molecular and Cellular Biology

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Although the roles of Jak-Stat pathways in type I and II interferon (IFN)-dependent transcriptional regulation are well established, the precise mechanisms of mRNA translation for IFN-sensitive genes remain to be defined. We examined the effects of IFNs on the phosphorylation/activation of eukaryotic translation initiation factor 4B (eIF4B). Our data show that eIF4B is phosphorylated on Ser422 during treatment of sensitive cells with alpha IFN (IFN-␣) or IFN-␥. Such phosphorylation is regulated, in a cell type-specific manner, by either the p70 S6 kinase (S6K) or the p90 ribosomal protein S6K (RSK) and results in enhanced interaction of the protein with eIF3A (p170/eIF3A) and increased associated ATPase activity. Our data also demonstrate that IFN-inducible eIF4B activity and IFN-stimulated gene 15 protein (ISG15) or IFN-␥-inducible chemokine CXCL-10 protein expression are diminished in S6k1/S6k2 double-knockout mouse embryonic fibroblasts. In addition, IFN-␣-inducible ISG15 protein expression is blocked by eIF4B or eIF3A knockdown, establishing a requirement for these proteins in mRNA translation/protein expression by IFNs. Importantly, the generation of IFN-dependent growth inhibitory effects on primitive leukemic progenitors is dependent on activation of the S6K/eIF4B or RSK/eIF4B pathway. Taken together, our findings establish critical roles for S6K and RSK in the induction of IFN-dependent biological effects and define a key regulatory role for eIF4B as a common mediator and integrator of IFN-generated signals from these kinases.Extensive work over the years has established that the control of initiation of mRNA translation occurs primarily at the step at which the 40S ribosomal subunit is recruited to mRNA, to be positioned at the initiation codon (15). Most eukaryotic mRNAs contain a 5Ј cap structure (m7GpppN) to which the cap-binding protein complex eukaryotic initiation factor 4F (eIF4F) is attached. eIF4F is composed of three subunits: eIF4E, the cap-binding subunit; eIF4A, a protein with RNA helicase activity that unwinds the mRNA 5Ј secondary structure; and eIF4G, a scaffolding protein that associates with other IFs (15,18,20,37,54). The unphosphorylated/activated form of the translational repressor 4E-BP1 (eIF4E-binding protein 1) competes with eIF4G for binding to eIF4E and blocks cap-dependent mRNA translation (37), while such 4E-BP1-eIF4E interactions are decreased when phosphorylation of 4E-BP1 occurs by the mammalian target of rapamycin (mTOR) kinase (15,18,20,37,54). Beyond phosphorylation of 4E-BP1, mTOR regulates activation of the p70 S6 kinase (S6K), which in turn phosphorylates several substrates, including the S6 ribosomal protein (rpS6), eIF4B, and the tumor suppressor PDCD4 (13,18,20,54).Although much is known about the roles of mTOR-generated signals in the control of mRNA translation for cytokines and growth factors, the roles of various mTOR effectors in the initiation of mRNA translation in response to interferons (IFNs) remain to be precisely defined. Type I (␣, ␤, ε, , and ) and I...

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Section: Discussionmentioning

confidence: 99%

Interferon-Dependent Engagement of Eukaryotic Initiation Factor 4B via S6 Kinase (S6K)- and Ribosomal Protein S6K-Mediated Signals

Kroczyńska

Kaur

Katsoulidis

et al. 2009

Molecular and Cellular Biology

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“…Initiation factor eIF3 is complex because some of its 13 putative subunits are either overexpressed or downregulated in human tumors (for a complete review on eIF3 see Dong and Zhang, 2006; Figure 3). For instance, amplification of the subunits eIF3-p110 in testicular cancers and eIF3-p40 in breast and prostate cancers have been reported whereas promoter hypermethylation likely accounts for the reduced level of eIF3-p48 subunit in non-small cell lung cancers (Nupponen et al, 2000;Okamoto et al, 2003;Buttitta et al, 2005).…”

Section: Other Translational Componentsmentioning

confidence: 99%

Mechanisms of translational deregulation in human tumors and therapeutic intervention strategies

Bilanges

Stokoe

2007

Oncogene

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“…eIF3 is the most complex translation initiation factor, consisting of 13 putative subunits named as eIF3a to eIF3m (16,17). eIF3 plays a critical role in all translation initiation steps.…”

Section: Introductionmentioning

confidence: 99%

Effect of eIF3a on Response of Lung Cancer Patients to Platinum-Based Chemotherapy by Regulating DNA Repair

Yin

Shen

Dong

et al. 2011

Clinical Cancer Research

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Purpose: The purpose of this study is to test the hypothesis that eIF3a may regulate the expression of DNA repair proteins which, in turn, affects response of lung cancer patients to treatments by DNAdamaging anticancer drugs.Experimental Design: Immunohistochemistry was used to determine the expression of eIF3a in 211 human lung cancer tissues followed by association analysis of eIF3a expression with patient's response to platinum-based chemotherapy. Ectopic overexpression and RNA interference knockdown of eIF3a were carried out in NIH3T3 and H1299 cell lines, respectively, to determine the effect of altered eIF3a expression on cellular response to cisplatin, doxorubicine, etoposide (VP-16), vincristine, and vinblastine by using MTT assay. The DNA repair capacity of these cells was evaluated by using host-cell reactivation assay. Real-time reverse transcriptase PCR and Western Blot analyses were carried out to determine the effect of eIF3a on the DNA repair genes by using cells with altered eIF3a expression.Results: eIF3a expression associates with response of lung cancer patients to platinum-based chemotherapy. eIF3a knockdown or overexpression, respectively, increased and decreased the cellular resistance to cisplatin and anthrocycline anticancer drugs, DNA repair activity, and expression of DNA repair proteins.Conclusions: eIF3a plays an important role in regulating the expression of DNA repair proteins which, in turn, contributes to cellular response to DNA-damaging anticancer drugs and patients' response to platinum-based chemotherapy. Clin Cancer Res; 17(13); 4 -9. Ó2011 AACR.

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Initiation factor eIF3 and regulation of mRNA translation, cell growth, and cancer

Cited by 130 publications

References 128 publications

Interferon-Dependent Engagement of Eukaryotic Initiation Factor 4B via S6 Kinase (S6K)- and Ribosomal Protein S6K-Mediated Signals

Interferon-Dependent Engagement of Eukaryotic Initiation Factor 4B via S6 Kinase (S6K)- and Ribosomal Protein S6K-Mediated Signals

Mechanisms of translational deregulation in human tumors and therapeutic intervention strategies

Effect of eIF3a on Response of Lung Cancer Patients to Platinum-Based Chemotherapy by Regulating DNA Repair

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