The DOI matches its Crossref record; 48 of the 50 references it cites were found in a registry or an index.
4E-BP1 Is a Key Effector of the Oncogenic Activation of the AKT and ERK Signaling Pathways that Integrates Their Function in Tumors
Open accessAbstract
PIK3CA and PTEN alterations are common in human cancer, but only a fraction of such tumors are dependent upon AKT signaling. AKT independence is associated with redundant activation of cap-dependent translation mediated by convergent regulation of the translational repressor 4E-BP1 by the AKT and ERK pathways. This provides mechanistic bases for the limited activity of AKT and MEK inhibitors in tumors with comutation of both pathways and the profound synergy observed with combined inhibition. Whereas such tumors are sensitive to a dominant active 4E-BP1 mutant, knockdown of 4E-BP1 expression reduces their dependence on AKT/ERK signaling for translation or survival. Thus, 4E-BP1 plays a prominent role in mediating the effects of these pathways in tumors in which they are activated by mutation.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“This is consistent with previous reports and with our previous finding that anti-proliferative efficacy requires dephosphorylation of 4E-BP1 and its consequent inhibition of cap-dependent translation15.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [15]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“We have previously shown that combined inhibition of MEK and AKT attenuates the growth of KRAS tumors and that this is dependent on suppression of 4E-BP1 phosphorylation15.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [15]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“We have previously shown that the PI3K/AKT/mTOR and RAS/RAF/ERK pathways converge on key cellular processes, including Cyclin D-Cdk4/6 activation and cap-dependent translation and that both pathways must be inhibited to affect tumor growth or survival15,24.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [15]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“We have previously shown that AKT and MEK inhibition cooperate to inhibit 4E-BP1 phosphorylation and that dephosphorylation of 4E-BP1 is required for the anti-tumor activity of the combination15.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [15]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“These data are consistent with our previous findings that 4E-BP1 is a convergent target of PI3K/AKT/mTOR and RAF/MEK/ERK pathways and integrates their function at the level of regulation of cap-dependent translation15.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [15]
The cited source says what the claim attributes to it.
In the citing paper
“Nevertheless, these data are consistent with our previous findings that inhibition of the growth of tumors in which ERK and PI3K/mTOR signaling are dysregulated requires inhibition of both pathways15,24.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [15]
The cited source says what the claim attributes to it.
In the citing paper
“We have previously shown that several downstream processes are under the control of both ERK and PI3K/mTOR signaling and that their effective inhibition requires inhibition of both pathways15,24.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [15]
The cited source says what the claim attributes to it.
In the citing paper
“This finding is consistent with a report suggesting that other KRAS-regulated pathways, in addition to MEK-ERK, contribute to phosphorylation of 4EBP1(45).”
From mTOR Inhibition Specifically Sensitizes Colorectal Cancers with KRAS or BRAF Mutations to BCL-2/BCL-XL Inhibition by Suppressing MCL-1 (2014) · cites this paper as [45]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
1 retracted
She, Q., Chandarlapaty, S., Ye, Q., Lobo, J. M., Haskell, K., Leander, K. R., Defeo-Jones, D., Huber, H. E., & Rosen, N. X. (2008) · PLoS ONE · doi:10.1371/journal.pone.0003065 · Cited by 313
Self-citationRetractedChou, T.-C., & Talalay, P. (1984) · Advances in Enzyme Regulation · doi:10.1016/0065-2571(84)90007-4 · Cited by 7,178
Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex
Sarbassov, D. D., Guertin, D. A., Ali, S. M., & Sabatini, D. M. (2005) · Science · doi:10.1126/science.1106148 · Cited by 6,216
The phosphatidylinositol 3-Kinase–AKT pathway in human cancer
Vivanco, I., & Sawyers, C. L. (2002) · Nature reviews. Cancer · doi:10.1038/nrc839 · Cited by 6,155
AKT/PKB signaling: navigating downstream
Manning, B. D., & Cantley, L. C. (2007) · Cell · doi:10.1016/j.cell.2007.06.009 · Cited by 6,115
High Frequency of Mutations of the PIK3CA Gene in Human Cancers
Samuels, Y., Wang, Z., Bardelli, A., Silliman, N., Ptak, J., Szabo, S., Yan, H., Gazdar, A. F., Powell, S. M., Riggins, G. J., et al. (2004) · Science · doi:10.1126/science.1096502 · Cited by 3,448
Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance
McCubrey, J. A., Steelman, L. S., Chappell, W. H., Abrams, S. L., Wong, E. W. T., Chang, F., Lehmann, B. D., Terrian, D. M., Milella, M., Tafuri, A., et al. (2006) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2006.10.001 · Cited by 2,349
Ras, PI(3)K and mTOR signalling controls tumour cell growth
Shaw, R. J., & Cantley, L. C. (2006) · Nature · doi:10.1038/nature04869 · Cited by 2,019
Thoreen, C. C., Kang, S. A., Chang, J. W., Liu, Q., Zhang, J., Gao, Y., Reichling, L. J., Sim, T., Sabatini, D. M., & Gray, N. S. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m900301200 · Cited by 1,803
Manning, B. D., Tee, A. R., Logsdon, M. N., Blenis, J., & Cantley, L. C. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00568-3 · Cited by 1,555
Cited by
Sorted by citations
Items 201–300 of 401
Modulation of 4E-BP1 Function as a Critical Determinant of Enzastaurin-Induced Apoptosis
Dumstorf, C. A., Konicek, B. W., McNulty, A. M., Parsons, S. H., Furic, L., Sonenberg, N., & Graff, J. R. (2010) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-10-0413 · Cited by 32
Yoshida, Y., Tsunoda, T., Doi, K., Fujimoto, T., Tanaka, Y., Ota, T., Ogawa, M., Matsuzaki, H., Kuroki, M., Iwasaki, A., et al. (2012) · PubMed · Cited by 32
Self-citationOncogenic β-catenin and PIK3CA instruct network states and cancer phenotypes in intestinal organoids
Riemer, P., Rydenfelt, M., Marks, M., van Eunen, K., Thedieck, K., Herrmann, B. G., Blüthgen, N., Sers, C., & Morkel, M. (2017) · The Journal of Cell Biology · doi:10.1083/jcb.201610058 · Cited by 31
“4EBP1 has previously been identified as a converging point of MEK–ERK and PI3K– AKT signals for cancer cell survival (She et al., 2010), and our analysis is in line with such a key role.”
BackgroundBeta-catenin cleavage enhances transcriptional activation
Goretsky, T., Bradford, E. M., Ye, Q., Lamping, O. F., Vanagunas, T., Moyer, M. P., Keller, P. C., Sinh, P., Llovet, J. M., Gao, T., et al. (2018) · Scientific Reports · doi:10.1038/s41598-017-18421-8 · Cited by 32
“Tumor dimensions were measured using a caliper and tumor volumes were calculated as mm 3 = π /6 × (larger diameter) × (smaller diameter) 2,43 .”
MethodSelf-citation4E-BP restrains eIF4E phosphorylation
Müller, D., Lasfargues, C., Khawand, S. E., Alard, A., Schneider, R. J., Bousquet, C., Pyronnet, S., & Martineau, Y. (2013) · Translation · doi:10.4161/trla.25819 · Cited by 31
“Consistently, overexpression of 4E-BP prevents eIF4E-induced tumorigenesis.(12,13) The interaction of 4E-BP with eIF4E is however precluded when 4E-BP is phosphorylated by mTOR,(14) a kinase which lies downstream of the growth-factor-dependent PI3K/AKT pathway.”
BackgroundInhibition of tumor cell growth by Sigma1 ligand mediated translational repression
Kim, F. J., Schrock, J. M., Spino, C. M., Marino, J. C., & Pasternak, G. W. (2012) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2012.08.052 · Cited by 31
“The cellular protein synthesis apparatus is a compelling target for therapeutic intervention in cancer, and considerable effort has been made toward developing agents to inhibit its components [18,19,23,24,25].”
BackgroundInfluentialDing, M., van der Kwast, T., Vellanki, R. N., Foltz, W. D., McKee, T. D., Sonenberg, N., Pandolfi, P. P., Koritzinsky, M., & Wouters, B. G. (2018) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-17-0696 · Cited by 28
Thomé, C. H., dos Santos, G. A., Ferreira, G. A., Scheucher, P. S., Izumi, C., Leopoldino, A. M., Simão, A. M., Ciancaglini, P., de Oliveira, K. T., Chin, A. P., et al. (2012) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m112.019661 · Cited by 33
“Indeed, phosphorylation of 4EBP-1 and ribosomal S6 kinase (RS6K) and up-regulation of cap-dependent translation in the ribosome is downstream of PI3K/AKT/mTOR (51, 67, 68).”
BackgroundFritsche‐Guenther, R., Zasada, C., Mastrobuoni, G., Royla, N., Rainer, R. J., Roßner, F., Pietzke, M., Klipp, E., Sers, C., & Kempa, S. (2018) · Scientific Reports · doi:10.1038/s41598-018-27394-1 · Cited by 31
Let-7 Sensitizes KRAS Mutant Tumor Cells to Chemotherapy
Dai, X., Jiang, Y., & Tan, C. (2015) · PLoS ONE · doi:10.1371/journal.pone.0126653 · Cited by 29
“A number of strategies have been pursued in order to thwart KRAS-driven oncogenesis, including the combination of kinase inhibitors (such as PI3K and MEK inhibitors) to simultaneously repress downstream RAS effectors [2,3], the inhibitors that directly attenuate the kinase activity of mutant KRAS [4,5], and the small…”
BackgroundAwasthi, N., Zhang, C., Hinz, S., Schwarz, M. A., & Schwarz, R. E. (2013) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/1756-9966-32-12 · Cited by 28
“In the present study, we evaluated the effect of sorafenib on phospho-p-70S6K and phospho-4E-BP1 as these proteins have recently been shown to be downstream effectors of both AKT/ mTOR and MEK/ERK signaling cascades [33].”
BackgroundZhou, S., Xia, H., Xu, H., Tang, Q., Nie, Y., Gong, Q., & Bi, F. (2018) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-018-0862-8 · Cited by 28
Jeong, J.-H., Jeong, Y., Cho, H., Shin, J., Kang, J. H., Park, K., Park, Y., Chung, I., Chang, H., Magae, J., et al. (2011) · Journal of Cellular Biochemistry · doi:10.1002/jcb.24001 · Cited by 28
“AKT mutation constructs expressed in human embryonic kidney cells demonstrate that activation of AKT is necessary and sufficient for 4E-BP1 phosphorylation but not for S6K phosphoryation [She et al., 2010].”
BackgroundRegulation of protein translation initiation in response to ionizing radiation
Trivigno, D., Bornes, L., Huber, S. M., & Rudner, J. (2013) · Radiation Oncology · doi:10.1186/1748-717x-8-35 · Cited by 26
“Phosphorylation of 4EBP1 is regulated by the Akt/mTOR pathway [2,13].”
BackgroundTherapeutic potentials of short interfering RNAs
Tam, C., Wong, J. H., Cheung, R. C. F., Zuo, T., & Ng, T. B. (2017) · Applied Microbiology and Biotechnology · doi:10.1007/s00253-017-8433-z · Cited by 27
Marques, A. E. M., Elias, S. T., Porporatti, A. L., CASTILHO, R. M., SQUARIZE, C. H., Canto, G. D. L., & Guerra, E. N. S. (2015) · Journal of Oral Pathology and Medicine · doi:10.1111/jop.12390 · Cited by 27
Zapevalova, M. V., Shchegravina, E. S., Fonareva, I. P., Salnikova, D. I., Sorokin, D. V., Scherbakov, A. M., Maleev, A. A., Ignatov, S. K., Grishin, I. D., Kuimov, A. N., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231810854 · Cited by 29
Attacking a Nexus of the Oncogenic Circuitry by Reversing Aberrant eIF4F-Mediated Translation
Bitterman, P. B., & Polunovsky, V. A. (2012) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-11-0530 · Cited by 26
Qu, Y., Zhao, R., Wang, H., Chang, K. S., Yang, X., Zhou, X., Dai, B., Zhu, Y., Shi, G., Zhang, H., et al. (2016) · Scientific Reports · doi:10.1038/srep23594 · Cited by 26
Sadowski, S. M., Boufraqech, M., Zhang, L., Mehta, A. R., Kapur, P., Zhang, Y., Li, Z., Shen, M., & Kebebew, E. (2015) · Oncotarget · doi:10.18632/oncotarget.3833 · Cited by 25
“Torin2 inhibited cellular migration and inhibited the phosphorylation of key effectors of the mTOR-pathway (AKT, 4E-BP1 and 70S6K), as well as claspin and survivin expression, regulators of cell cycle and apoptosis.”
BackgroundInfluentialAl-Qasem, A. J., Al‐Howail, H. A., Al‐Swailem, M., Al‐Mazrou, A., Al‐Otaibi, B., Al‐Jammaz, I., Al‐Khalaf, H. H., & Aboussekhra, A. (2015) · Molecular Carcinogenesis · doi:10.1002/mc.22271 · Cited by 25
Chen, K., Yang, J., Li, J., Wang, X., Chen, Y., Huang, S., & Chen, J. (2016) · Oncotarget · doi:10.18632/oncotarget.7164 · Cited by 26
“By the software analysis [30], we found that the combined index (CI) values for the combination of SMI4a and LY294002 at different concentrations were all less than 1 (Figure 4B), indicating that this combination induces strong synergic apoptosis in K562 cells.”
BackgroundLi, X., Li, B., Ni, Z., Zhou, P., Wang, B., He, J., Xiong, H., Yang, F., Wu, Y., Lyu, X., et al. (2017) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-16-0763 · Cited by 23
“These findings were consistent with the previous reports that activating 4EBP1 or disturbing EIF4F assembly plays a central role in strengthening the collaborative targeted cancer therapeutics (15, 36).”
ResultKu, B. M., Jho, E. H., Bae, Y.-H., Sun, J., Ahn, J. S., Park, K., & Ahn, M. (2014) · Investigational New Drugs · doi:10.1007/s10637-014-0163-9 · Cited by 25
Immunohistochemical and molecular analysis of PI3K/ AKT /m TOR pathway in esophageal carcinoma
Tasioudi, K. E., Sakellariou, S., Levidou, G., Theodorou, D., Michalopoulos, N. V., Patsouris, E., Korkolopoulou, P. A., & Saetta, A. A. (2015) · Apmis · doi:10.1111/apm.12398 · Cited by 24
“could be explained by a recently described interconnection between MAPK pathway and 4E-BP1 suggesting that 4E-BP1 is serving as an effector for both AKT and MAPK proteins (33, 34).”
BackgroundChao, M., Wang, L., Lai, C.-Y., Yang, X.-M., Cheng, Y., Lee, K., Pan, S., & Teng, C. (2015) · Oncotarget · doi:10.18632/oncotarget.4483 · Cited by 23
“Therefore, p-4E-BP1 is regarded as a proto-oncogene and even as a “funnel factor” in human cancers [21].”
PI 3K‐dependent multiple myeloma cell survival is mediated by the PIK 3 CA isoform
Hofmann, C., Stühmer, T., Schmiedl, N., Wetzker, R., Mottok, A., Rosenwald, A., Langer, C., Zovko, J., Chatterjee, M., Einsele, H., et al. (2014) · British Journal of Haematology · doi:10.1111/bjh.12920 · Cited by 23
“Convergence of the MEK/MAPK and PI3K/Akt pathways to regulate common downstream effectors as well as crosstalk between these pathways are well described in the cancer literature (She et al, 2010; Mendoza et al, 2011).”
BackgroundYeh, C., Chuang, W., Chao, Y., Liu, Y., Chang, Y., Kuo, S., Tseng, C., Chang, H., & Hsueh, C. (2010) · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin · doi:10.1007/s00428-010-0994-5 · Cited by 23
“Since 4E-BP1 receives convergent signals from both AKT/mTOR to MAPK pathways [ 22 ], p-4E-BP1 could well be a better indicator of oncogenic signaling than p-mTOR or p-AKT.”
BackgroundTong, X., Yu, G., Fu, X., Song, R., Gu, J., & Liu, Z. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23179846 · Cited by 23
Santasusagna, S., Zhu, S., Jawalagatti, V., Carceles-Cordon, M., Ertel, A., Garcia‐Longarte, S., Song, W., Fujiwara, N., Li, P., Mendizabal, I., et al. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-23-0306 · Cited by 24
Coffman, K., Yang, B., Lu, J., Tetlow, A. L., Pelliccio, E., Lu, S., Guo, D., Tang, C., Dong, M., & Tamanoi, F. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.482067 · Cited by 22
“In cancer cells, it is believed that 4E-BP1 has an important role in growth and proliferation (13, 14).”
BackgroundNishikawa, M., Miyake, H., Harada, K., & Fujisawa, M. (2013) · Medical Oncology · doi:10.1007/s12032-013-0792-4 · Cited by 22
“Although 4E-BP1 is one of the main downstream molecules phosphorylated by mTOR, recently accumulated evidence strongly suggests that other kinases may also be implicated in the phosphorylation of 4E-BP-1, such as those involved in the mitogen-activated protein kinase pathway [19, 20].”
BackgroundKanda, T., Ozawa, M., & Tsukiyama–Kohara, K. (2016) · BMC Veterinary Research · doi:10.1186/s12917-016-0694-8 · Cited by 22
“Furthermore, 4E-BP1 was previously shown to be involved in other cell activities such as regulation of cell growth and oncogenesis [39, 40].”
BackgroundUpregulation of EphB3 in gastric cancer with acquired resistance to a FGFR inhibitor
Lee, S., Na, Y. J., Jeong, Y. A., Kim, J. L., Oh, S. C., & Lee, D.-H. (2018) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2018.07.008 · Cited by 23
Milton, C. K., Self, A. J., Clarke, P. A., Banerji, U., Piccioni, F., Root, D. E., & Whittaker, S. R. (2020) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-19-1131 · Cited by 21
“Multiple oncogenic pathways are engaged downstream of KRAS (17, 18), so it is perhaps unsurprising that targeting a single downstream effector may not be enough to affect cell viability.”
BackgroundYin, J., Chen, J., Hong, J. H., Huang, Y., Xiao, R., Liu, S., Deng, P., Sun, Y.-C., Chai, K. X. Y., Zeng, X., et al. (2024) · JCI Insight · doi:10.1172/jci.insight.177857 · Cited by 23
“A previous study has shown that combined inhibition of AKT and MEK kinase can cause the recruitment of 4EBP1 to suppress cap-dependent translation (28).”
BackgroundAmyloid Precursor Protein (APP) Affects Global Protein Synthesis in Dividing Human Cells
Sobol, A., Galluzzo, P., Liang, S., Rambo, B., Skucha, S., Weber, M. J., Alani, S., & Bocchetta, M. (2014) · Journal of Cellular Physiology · doi:10.1002/jcp.24835 · Cited by 21
Bonnas, C., Specht, K., Spleiss, O., Froehner, S., Dietmann, G., Krüger, J. M., Arbogast, S., & Feuerhake, F. (2011) · International Journal of Cancer · doi:10.1002/ijc.27422 · Cited by 21
“It has been postulated, that in cells with coexistent mutational activation of PI3K/AKT and ERK pathways, inhibition of both is required to inhibit growth, whereas blocking of either one pathway causes the tumor to become dependent on the other.(30) Thus, cell lines with coexistent KRAS/BRAF and PIK3CA/PTEN mutation w…”
BackgroundBitterman, P. B., & Polunovsky, V. A. (2012) · Cell Cycle · doi:10.4161/cc.11.6.19610 · Cited by 23
Inhibition of mTOR/S6K1/4E-BP1 Signaling by Nutraceutical SIRT1 Modulators
Bianchi, S. E., & Giovannini, L. (2018) · Nutrition and Cancer · doi:10.1080/01635581.2018.1446093 · Cited by 20
Chakravarthy, R., Clemens, M. J., Pirianov, G., Perdios, N., Mudan, S., Cartwright, J. E., & Elia, A. (2013) · Biology of the Cell · doi:10.1111/boc.201300021 · Cited by 21
“, 2009) and changes in the levels of 4E-BP1 can affect the ability of tumourigenic cells to undergo apoptosis (Jeffrey et al., 2006; She et al., 2010; Nishioka et al., 2010).”
BackgroundDiscovery of a Novel B-Raf Fusion Protein Related to c-Met Drug Resistance
Dillon, R., Nilsson, C. L., Shi, S. D. ‐., Lee, N. V., Krastins, B., & Greig, M. J. (2011) · Journal of Proteome Research · doi:10.1021/pr200498v · Cited by 20
Dolgikh, N., Hugle, M., Vogler, M., & Fulda, S. (2018) · Cancer Research · doi:10.1158/0008-5472.can-17-1737 · Cited by 19
Cunningham, D. L., Sarhan, A. R., Creese, A. J., Larkins, K. P. B., Zhao, H., Ferguson, H. R., Brookes, K., Marusiak, A. A., Cooper, H. J., & Heath, J. K. (2020) · Scientific Reports · doi:10.1038/s41598-020-64534-y · Cited by 20
Targeting transcription of MCL-1 sensitizes HER2-amplified breast cancers to HER2 inhibitors
Floros, K. V., Jacob, S., Kurupi, R., Fairchild, C. K., Hu, B., Puchalapalli, M., Koblinski, J. E., Dozmorov, M. G., Boikos, S. A., Scaltriti, M., et al. (2021) · Cell Death and Disease · doi:10.1038/s41419-021-03457-6 · Cited by 20
Characteristics and molecular mechanism of drug-tolerant cells in cancer: a review
Liang, X.-W., Liu, B., Chen, J.-C., Cao, Z. W., Chu, F.-R., Xiong, L., Wang, S.-Z., & Wu, J. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1177466 · Cited by 20
Wang, Q., Feng, W., Li, C., Lv, G., Wang, G., Liu, T., Bellail, A. C., & Hao, C. (2013) · PLoS ONE · doi:10.1371/journal.pone.0073175 · Cited by 19
“the PI3K and mTOR pathway [57] and the incomplete inhibition by PP242 of the 4E-BP1 phosphorylation contributes to the carcinoma resistance to PP242 treatment [48].”
BackgroundRetractedPromotion of viral internal ribosomal entry site-mediated translation under amino acid starvation
Licursi, M., Komatsu, Y., Pongnopparat, T., & Hirasawa, K. (2012) · Journal of General Virology · doi:10.1099/vir.0.040386-0 · Cited by 19
The role of stearoyl-coenzyme A desaturase 1 in clear cell renal cell carcinoma
Wang, H., Zhang, Y., Lu, Y., Song, J., Huang, M., Zhang, J., & Huang, Y. (2015) · Tumor Biology · doi:10.1007/s13277-015-3451-x · Cited by 19
“Given that Ser473 of AKT molecule was not phosphorylated due to SCD-1 interference, the activation of downstream molecules of AKT was not detected, including two mTOR components: P70S6K1 [20] and 4E-BP1 [21].”
BackgroundNew insights into 4E-BP1-regulated translation in cancer progression and metastasis
Wang, J., Ye, Q., & She, Q. (2014) · Cancer Cell & Microenvironment · doi:10.14800/ccm.331 · Cited by 18
“We found that in PIK3CA mutant tumors, the AKT dependence of 4E-BP1 phosphorylation is closely correlated with tumor growth [28, 31].”
InfluentialSelf-citationSilva, J. M., Deuker, M. M., Baguley, B. C., & McMahon, M. (2017) · Pigment Cell & Melanoma Research · doi:10.1111/pcmr.12586 · Cited by 19
“…or its direct downstream effectors such as the AKT, serum-and glucocorticord-inducible protein kinase (SGK), or other effectors of PI30-lipid signaling (Cancer Genome Atlas, 2015; Hodis et al., 2012; She et al., 2010; Tessier and Woodgett, 2006; Vanhaesebroeck et al., 2012; Vasudevan et al., 2009).”
BackgroundTargeting integrin α2 as potential strategy for radiochemosensitization of glioblastoma
Korovina, I., Vehlow, A., Temme, A., & Cordes, N. (2022) · Neuro-Oncology · doi:10.1093/neuonc/noac237 · Cited by 19
Tracing cancer networks with phosphoproteomics
Solit, D. B., & Mellinghoff, I. K. (2010) · Nature Biotechnology · doi:10.1038/nbt1010-1028 · Cited by 18
Self-citationMeng, J., Zhou, X., Yang, J., Qu, X., & Cui, S. (2020) · Environmental Pollution · doi:10.1016/j.envpol.2020.114578 · Cited by 18
Immunogenic chemotherapy effectively inhibits KRAS-Driven lung cancer
Wang, D., Cong, J., Fu, B., Zheng, X., Sun, R., Tian, Z., & Wei, H. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.07.043 · Cited by 19
Selective inhibition reveals the regulatory function of DYRK2 in protein synthesis and calcium entry
Wei, T., Wang, J., Liang, R., Chen, W., Chen, Y., Ma, M., He, A., Du, Y., Zhou, W., Zhang, Z., et al. (2022) · eLife · doi:10.7554/elife.77696 · Cited by 18
Combined inhibition of MEK and mTOR has a synergic effect on angiosarcoma tumorgrafts
Andersen, N. J., BOGUSLAWSKI, E. B., Kuk, C. C., Chambers, C. M., & Duesbery, N. S. (2015) · International Journal of Oncology · doi:10.3892/ijo.2015.2989 · Cited by 18
“Phosphorylation of 4E-BP1 is reported to be regulated through both the MEK and mTOR pathways in MEK driven tumors (33,34).”
BackgroundEnhanced bypass of PD-L1 translation reduces the therapeutic response to mTOR kinase inhibitors
Cao, Y., Ye, Q., Ma, M., & She, Q. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112764 · Cited by 18
Self-citationNoncanonical feedback loop between “RIP3–MLKL” and “4EBP1–eIF4E” promotes neuronal necroptosis
Wang, S., Zhang, Y., Wang, M., Zhai, Z., Tan, Y., Xu, W., Ren, X., Hu, X., Mo, J., Liu, J., et al. (2025) · MedComm · doi:10.1002/mco2.70107 · Cited by 20
“42,43 These differences may be related to different microenvironments and diseases, suggesting selective translation of key proteins and perversion of cellular energy utilization during specific pathophysiological processes.”
Zou, Y., Wang, J., Leng, X., Huang, J., Xue, W., Zhang, J., & Huang, Y. (2017) · Oncotarget · doi:10.18632/oncotarget.15346 · Cited by 17
“Shimizu T, Tolcher AW, Papadopoulos KP, Beeram M, Rasco DW, Smith LS, Gunn S, Smetzer L, Mays TA, Kaiser B, Wick MJ, Alvarez C, Cavazos A, et al. The clinical effect of the dual-targeting strategy involving PI3K/ AKT/mTOR and RAS/MEK/ERK pathways in patients with advanced cancer.”
BackgroundResultInfluentialPan, X., Yang, X., Zang, J., Zhang, S., Huang, N. J., Guan, X., Zhang, J., Wang, Z., Li, X., & Lei, X. (2017) · Oncology Letters · doi:10.3892/ol.2017.6049 · Cited by 17
“The correct functioning of cellular processes, including drug resistance, is regulated by controling gene expression at the mRNA translational level (15,16).”
BackgroundCHEN, Y., WANG, J., FAN, H., Xie, J., Xu, L., & Zhou, B. (2017) · Neoplasma · doi:10.4149/neo_2017_518 · Cited by 17
“Therefore, both PI3K/AKT/mTOR and RAS/MAPK pathway contribute to the phosphorylation of 4E-BP1, which results in formation of the cap-dependent mRNA translation initiation complex [24, 25].”
BackgroundTsukamoto, T., Hama, S., Kogure, K., & Tsuchiya, H. (2013) · Experimental Cell Research · doi:10.1016/j.yexcr.2013.05.031 · Cited by 16
Multimodality Approaches to Treat Hypoxic Non-Small Cell Lung Cancer (NSCLC) Microenvironment
Liang, S., Galluzzo, P., Sobol, A., Skucha, S., Rambo, B., & Bocchetta, M. (2012) · Genes & Cancer · doi:10.1177/1947601912457025 · Cited by 16
“However, She et al.(29) have used a similar compound alone (100 mg/kg for 5 consecutive days per week) and in combination with a MEK inhibitor in nude mice for more than 20 days, obtaining slower tumor growth of subcutaneous xenograft models.”
MethodPSPC1 Potentiates IGF1R Expression to Augment Cell Adhesion and Motility
Jen, H., Gu, D.-L., Lang, Y., & Jou, Y. (2020) · Cells · doi:10.3390/cells9061490 · Cited by 17
“Overexpression of IGF1R activates canonical downstream targets PI3K/AKT and MAPK/ERK signaling [18], that are critical for tumorigenic functions including cell growth, survival, migration, epithelial to mesenchymal transition (EMT), and drug resistance [19,20].”
BackgroundSong, J. M., Gallagher, E. E., Menon, A., Mishra, L. D., & Garner, A. L. (2019) · Organic & Biomolecular Chemistry · doi:10.1039/c9ob01041f · Cited by 16
Wang, X., Elshahawi, S. I., Ponomareva, L. V., Ye, Q., Liu, Y., Copley, G. C., Hower, J. C., Hatcher, B. E., Kharel, M. K., Lanen, S. G. V., et al. (2019) · Journal of Natural Products · doi:10.1021/acs.jnatprod.9b01015 · Cited by 16
Self-citationNovel small interfering RNA cotargeting strategy as treatment for colorectal cancer
Valentino, J. D., Elliott, V. A., Zaytseva, Y. Y., Rychahou, P. G., Mustain, W. C., Wang, C., Gao, T., & Evers, B. M. (2012) · Surgery · doi:10.1016/j.surg.2012.05.006 · Cited by 15
“4E-BP1 has recently been identified as a downstream effector of both the PI3K/AKT/mTOR and Ras pathways and integrates the function of these pathways.(14) In this present study, treatments that caused the greatest increase in apoptosis (KRAS and combination PIK3CA and KRAS siRNA treatments in the HCT116 cell line) cor…”
InfluentialLi, J., Cao, B., Zhou, S., Zhu, J., Zhang, Z., Hou, T., & Mao, X. (2013) · European Journal Of Haematology · doi:10.1111/ejh.12193 · Cited by 15
“Both p70S6K and 4EBP1 phosphorylations are regulated by the PI3K/AKT signaling (12, 28).”
BackgroundLi, J., Li, R., Ma, L.-R., Wang, P., Xu, D., Huang, J., Li, L.-Q., Tang, L. L., Xie, Y., Leung, E. L., et al. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.875330 · Cited by 17
Liu, T., Yang, K.-X., Yu, J., Cao, Y., Ren, J.-S., Hao, J., Pan, B.-Q., Ma, S., Yang, L.-Y., Cai, Y., et al. (2018) · Journal of Molecular Medicine · doi:10.1007/s00109-018-1663-4 · Cited by 15
Ma, Y., Sender, S., Sekora, A., Kong, W., Bauer, P., Ameziane, N., Al‐Ali, R., Krake, S., Radefeldt, M., Weiß, F. U., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23084295 · Cited by 14
“Consistent with these data, one study demonstrated that, in cell lines of colorectal cancer, lung cancer, breast cancer, and melanoma, KRAS mutations were associated with significant resistance to AKT1/2 inhibition [38].”
BackgroundResultCao, Y., Chong, Y., Shen, H., Zhang, M., Huang, J., Zhu, Y., & Zhang, Z. (2013) · Journal of Materials Chemistry B · doi:10.1039/c3tb20764a · Cited by 14
Du, Y., Long, Q., Shi, Y. Q., Liu, X., Li, X., Zeng, J., Gong, Y., Li, L., Wang, X., & He, D. (2015) · Oncology Reports · doi:10.3892/or.2015.4201 · Cited by 14
“Inhibition of mTOR activation is important in improving efficacy of both chemotherapy and radiotherapy (22).”
Jakopović, B., Horvatić, A., Klobučar, M., Gelemanović, A., Grbčić, P., Oršolić, N., Jakopovich, I., & Pavelić, S. K. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.01202 · Cited by 14
Brusatol Inhibits Tumor Growth and Increases the Efficacy of Cabergoline against Pituitary Adenomas
Wu, Z., Xu, Y., Xu, J., Lu, J., Cai, L., Li, Q., Wang, C., & Su, Z. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/6696015 · Cited by 14
Synthetic mRNAs; Their Analogue Caps and Contribution to Disease
Kyriakopoulos, A. M., & McCullough, P. A. (2021) · Diseases · doi:10.3390/diseases9030057 · Cited by 15
Zhu, H., Dai, C., He, L., Xu, A., & Chen, T. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.00946 · Cited by 14
“…is a downstream peptide in mammalian target of rapamycin (mTOR) critical pathway, which is a crucial regulator for cancer cells (Wolfson and Sabatini., 2017; Song et al., 2019; Woodcock et al., 2019), and belongs to a family of translation repressor proteins (Rojo et al., 2007; She et al., 2010).”
BackgroundLee, J., Lee, H., Yun, S., Jung, K. H., Jeong, Y., YAN, H. H., Hong, S., & Hong, S. (2012) · Cancer Letters · doi:10.1016/j.canlet.2012.10.028 · Cited by 13
Park, H., Lim, W., You, S., & Song, G. (2019) · Comparative Biochemistry and Physiology Part C Toxicology & Pharmacology · doi:10.1016/j.cbpc.2019.02.014 · Cited by 13
Monitoring flux in signalling pathways through measurements of 4EBP1-mediated eIF4F complex assembly
Frosi, Y., Usher, R., Lian, D. T. G., Lane, D. P., & Brown, C. J. (2019) · BMC Biology · doi:10.1186/s12915-019-0658-0 · Cited by 13
The 4E-BP1/eIF4E ratio is a determinant for rapamycin response in esophageal cancer cells
Hsu, H., Lin, M.-H., Jang, Y.-H., Kuo, T.-T., Liu, C., & Cheng, T.-H. (2014) · Journal of Thoracic and Cardiovascular Surgery · doi:10.1016/j.jtcvs.2014.09.047 · Cited by 13
Guo, X., Huang, S., Zhang, Y., Wang, H., Li, L., Ran, J., Chen, D., Li, X., & Li, J. (2024) · Journal of Natural Medicines · doi:10.1007/s11418-023-01769-9 · Cited by 13
“Crosstalk between MAPK and PI3K–AKT has been reported in various cancer types [7–9].”
Ferrari, K. L., de Camargo, J. A., Rocha, G. Z., Carvalheira, J. B. C., Saad, M. J. A., Billis, A., & Reis, L. O. (2014) · The Journal of Urology · doi:10.1016/j.juro.2014.08.106 · Cited by 12
“As such 4E-BP1 might be a suitable new molecular target when BCG fails since for tumor growth 4E-BP1 was suggested to integrate signals from the PI3K and MAPK signaling pathway.(15)”
BackgroundKeniry, M. E., & Parsons, R. E. (2011) · Cancer Discovery · doi:10.1158/2159-8290.cd-11-0157 · Cited by 12
Multifaceted control of mRNA translation machinery in cancer
Alboushi, L., Hackett, A. P., Naeli, P., Bakhti, M., & Jafarnejad, S. M. (2021) · Cellular Signalling · doi:10.1016/j.cellsig.2021.110037 · Cited by 13
Chronic Mechanistic Target of Rapamycin Inhibition: Preventing Cancer to Delay Aging, or Vice Versa?
Sharp, Z. D., Curiel, T. J., & Livi, C. B. (2013) · Interdisciplinary topics in gerontology and geriatrics · doi:10.1159/000343625 · Cited by 11
Mammary cancer promotion by ovarian hormones involves IGFR/AKT/mTOR signaling
Arumugam, A., Parada, J., & Lakshmanaswamy, R. (2012) · Steroids · doi:10.1016/j.steroids.2012.03.009 · Cited by 12
Han, H., Yang, M., Wen, Z., Mei, F., Chen, Q., Ma, Y., Lai, X., Zhang, Y., Fang, R., Yin, T., et al. (2024) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2024.107981 · Cited by 11
Insulin-IGF signaling affects cell transformation in the BALB/c 3T3 cell model
Poburski, D., Leovsky, C., Boerner, J. B., Szimmtenings, L., Ristow, M., Glei, M., & Thierbach, R. (2016) · Scientific Reports · doi:10.1038/srep37120 · Cited by 10
Wang, Q., Xia, X., Deng, X., Li, N., Wu, D., Zhang, L., Yang, C., Tao, F., & Zhou, J. (2015) · Journal of Environmental Sciences · doi:10.1016/j.jes.2015.04.037 · Cited by 11
“…protein translation via mammalian targeting of the rapamycin (mTOR) signaling pathway (LoPiccolo et al., 2008), and phosphorylated Akt results in the activation of eukaryotic initiation factor (eIF) 4E-binding protein 1 (4E-BP1), which relieves the translational repression (She et al., 2010).”
BackgroundFrosi, Y., Lin, Y., Jiang, S., Ramlan, S. R., Hew, K., Engman, A. H., Pillai, A., Yeung, K., Cheng, Y. X., Cornvik, T. C., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-32463-1 · Cited by 11
Sun, C., Yang, X., Jin, Z., & Gao, Z. (2022) · Journal of Chemotherapy · doi:10.1080/1120009x.2022.2091122 · Cited by 10
“The limited success of second generation mTOR inhibitors in cancer treatment is in part due to mTOR-independent 4E-BP1 phosphorylation [32].”
BackgroundPharmacologic Inhibition of SHP2 Blocks Both PI3K and MEK Signaling in Low-epiregulin HNSCC via GAB1
Kurupi, R., Floros, K. V., Jacob, S., Chawla, A. T., Cai, J., Hu, B., Puchalapalli, M., Coon, C. M., Khatri, R., Crowther, G. S., et al. (2022) · Cancer Research Communications · doi:10.1158/2767-9764.crc-21-0137 · Cited by 12
“Preclinically, we (38, 49, 50) and others (11, 35, 39, 51) have demonstrated the dual combination of MEK and PI3K signaling is highly efficacious across a”
BackgroundJin, L., Mi, T., Wu, X., Wang, Z., Zhang, Z., Liu, J., Wang, Z., Wang, J., Li, M., Ren, C., et al. (2023) · Cancers · doi:10.3390/cancers15072023 · Cited by 10
“The eIF4 B mediates mRNA and ribosome binding to initiate protein translation [41,42].”
BackgroundBullock, K. K., Shattuck-Brandt, R. L., Scalise, C. B., Luo, W., Chen, S., Saleh, N., Ericsson, P. I. G., Garcia, G., Sanders, M. E., Ayers, G. D., et al. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.216681 · Cited by 10
Lakiotaki, E., Levidou, G., Angelopoulou, M. K., Adamopoulos, C., Pangalis, G. A., Rassidakis, G. Z., Vassilakopoulos, T. P., Gainaru, G., Flevari, P., Sachanas, S. P., et al. (2016) · Scientific Reports · doi:10.1038/srep21252 · Cited by 10
Miao, Y., Chen, L., Shi, C., Fan, R.-G., Chen, P., Liu, H., Xia, A., & Qian, H. (2017) · Molecular Medicine Reports · doi:10.3892/mmr.2017.6352 · Cited by 10
“During tumorigenesis, 4E-BP1 is an effector for the oncogenic roles of ERK and AKT signaling pathways (30).”
Drug Combinatorial Therapies for the Treatment of KRAS Mutated Lung Cancers
He, H., Xu, C., Cheng, Z., Qian, X., & Zheng, L. (2019) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026619666190902150555 · Cited by 10
Qin, X., Li, W., Ali, S., Xu, M., Li, Y., Li, S., Meng, X., Liu, L., & Dong, L. (2021) · iScience · doi:10.1016/j.isci.2021.103528 · Cited by 11
“Although phosphorylation of 4EBP1 seems to be mainly controlled by the mTORC1 pathway, other unknown kinases (CDK1) or mechanisms (ATM/p53) also regulate its activity (She et al., 2010).”
Background
Metadata
- Authors
- She, Q.-B., Halilovic, E., Ye, Q., Zhen, W., Shirasawa, S., Sasazuki, T., Solit, D. B., & Rosen, N.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Fukuoka University (JP)
- Corresponding author
- Rosen, Neal
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2010-07
- Volume
- 18
- Issue
- 1
- Pages
- 39-51
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC3286650
- OpenAlex
- W2084875329
- Cited by
- 400
- References
- 50
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 16 · 2023: 12 · 2022: 21 · 2021: 17 · 2020: 11 · 2019: 16 · 2018: 23 · 2017: 26 · 2016: 22 · 2015: 33 · 2014: 45 · 2013: 42 · 2012: 49
- FWCI
- 18.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P01CA129243, P01CA094060)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- 4E-BP1, Akt signaling, ERK signaling, PIK3CA mutation, PTEN loss, cap-dependent translation, translational repressor, MEK inhibitors, AKT inhibitors, combination therapy synergy, oncogene activation
- MeSH terms
- Phosphoinositide-3 Kinase Inhibitors, Animals, Colonic Neoplasms, Female, Humans, Mice, Nude, Mutation, Phosphoproteins, RNA, Messenger, Protein Biosynthesis, Tumor Cells, Cultured, Blotting, Western, Signal Transduction, Survival Rate, Apoptosis, Cell Cycle Proteins, Phosphatidylinositol 3-Kinases, Reverse Transcriptase Polymerase Chain Reaction, RNA, Small Interfering, Extracellular Signal-Regulated MAP Kinases, Adaptor Proteins, Signal Transducing, Cell Proliferation, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Mice, Class I Phosphatidylinositol 3-Kinases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
