Rare codons capacitate Kras-driven de novo tumorigenesis

Pershing, Nicole L.K.; Lampson, Benjamin L.; Belsky, Jason A.; Kaltenbrun, Erin; MacAlpine, David M.; Counter, Christopher M.

doi:10.1172/jci77627

Cited by 77RNA and protein synthesis mechanismsProtein Kinase Regulation and GTPase SignalingCancer Genomics and Diagnostics

Rare codons capacitate Kras-driven de novo tumorigenesis

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Pershing, Nicole L.K., Lampson, Benjamin L., Belsky, Jason A., Kaltenbrun, Erin, MacAlpine, David M., Counter, Christopher M.·2015·Journal of Clinical Investigation

DOI 10.1172/jci77627PMC PMC4382256

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Abstract

The KRAS gene is commonly mutated in human cancers, rendering the encoded small GTPase constitutively active and oncogenic. This gene has the unusual feature of being enriched for rare codons, which limit protein expression. Here, to determine the effect of the rare codon bias of the KRAS gene on de novo tumorigenesis, we introduced synonymous mutations that converted rare codons into common codons in exon 3 of the Kras gene in mice. Compared with control animals, mice with at least 1 copy of this Kras(ex3op) allele had fewer tumors following carcinogen exposure, and this allele was mutated less often, with weaker oncogenic mutations in these tumors. This reduction in tumorigenesis was attributable to higher expression of the Kras(ex3op) allele, which induced growth arrest when oncogenic and exhibited tumor-suppressive activity when not mutated. Together, our data indicate that the inherent rare codon bias of KRAS plays an integral role in tumorigenesis.

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Additional biochemical, structural, and signaling distinctions have been identified between different mutant KRAS alleles, including between those at the same amino acid position.
“Additional biochemical, structural, and signaling distinctions have been identified between different mutant alleles, including between those at the same amino acid position4,8,13–20.”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [13]

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NIH Image to ImageJ: 25 years of image analysis
Schneider, C. A., Rasband, W. S., & Eliceiri, K. W. (2012) · Nature Methods · doi:10.1038/nmeth.2089 · Cited by 64,638 · see citing works
Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D., & Lowe, S. W. (1997) · Cell · doi:10.1016/s0092-8674(00)81902-9 · Cited by 5,178 · cited 15× · see citing works
“Immunoblot analysis revealed the expected robust expression of FLAG-HRAS G12V (4) and higher expression of FLAG-KRAS in cells transduced with oncogenic FLAG-Kras ex3op transgenes compared with those transduced with the FLAG-Kras nat counterparts with the same oncogenic mutations.”
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Sharp, P. M., & Li, W.-H. (1987) · Nucleic Acids Research · doi:10.1093/nar/15.3.1281 · Cited by 3,992 · see citing works
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Kimchi-Sarfaty, C., Oh, J. M., Kim, I.-W., Sauna, Z. E., Calcagno, A. M., Ambudkar, S. V., & Gottesman, M. M. (2007) · Science · doi:10.1126/science.1135308 · Cited by 2,416 · see citing works
Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis
DeNicola, G. M., Karreth, F. A., Humpton, T. J., Gopinathan, A., Wei, C., Frese, K., Mangal, D., Yu, K. H., Yeo, C. J., Calhoun, E. S., et al. (2011) · Nature · doi:10.1038/nature10189 · Cited by 2,277 · see citing works
Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-rasPreprint
Jackson, E. L., Willis, N. A., Mercer, K. L., Bronson, R. T., Crowley, D. G., Montoya, R., Jacks, T., & Tuveson, D. A. (2001) · Genes & Development · doi:10.1101/gad.943001 · Cited by 1,877 · see citing works
RAS oncogenes: weaving a tumorigenic web
Pylayeva-Gupta, Y., Grabocka, E., & Bar-Sagi, D. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3106 · Cited by 1,789 · see citing works
Synonymous but not the same: the causes and consequences of codon bias
Plotkin, J. B., & Kudla, G. (2010) · Nature Reviews Genetics · doi:10.1038/nrg2899 · Cited by 1,677 · see citing works
Role of the INK4a Locus in Tumor Suppression and Cell Mortality
Serrano, M., Lee, H.-W., Chin, L., Cordon-Cardo, C., Beach, D., & DePinho, R. A. (1996) · Cell · doi:10.1016/s0092-8674(00)81079-x · Cited by 1,585 · see citing works
The Ras-RasGAP Complex: Structural Basis for GTPase Activation and Its Loss in Oncogenic Ras Mutants
Scheffzek, K., Ahmadian, M. R., Kabsch, W., Wiesmüller, L., Lautwein, A., Schmitz, F., & Wittinghofer, A. (1997) · Science · doi:10.1126/science.277.5324.333 · Cited by 1,543 · see citing works
Senescence in premalignant tumours
Collado, M., Gil, J., Efeyan, A., Guerra, C., Schuhmacher, A. J., Barradas, M., Benguría, A., Zaballos, A., Flores, J. M., Barbacid, M., et al. (2005) · Nature · doi:10.1038/436642a · Cited by 1,482 · see citing works
Acre-transgenic mouse strain for the ubiquitous deletion ofloxP-flanked gene segments including deletion in germ cells
Schwenk, F., Baron, U., & Rajewsky, K. (1995) · Nucleic Acids Research · doi:10.1093/nar/23.24.5080 · Cited by 1,289 · see citing works
Codon usage tabulated from international DNA sequence databases: status for the year 2000
Nakamura, Y. (2000) · Nucleic Acids Research · doi:10.1093/nar/28.1.292 · Cited by 1,259 · see citing works
Senescence in tumours: evidence from mice and humans
Collado, M., & Serrano, M. (2010) · Nature Reviews Cancer · doi:10.1038/nrc2772 · Cited by 1,124 · cited 3× · see citing works
“Growth arrest in response to oncogenic stress induced by oncogenic RAS is largely attributed to stimulation of the MAPK pathway (9).”
Influential
Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma
Aguirre, A. J., Bardeesy, N., Sinha, M., Lopez, L., Tuveson, D. A., Horner, J., Redston, M. S., & DePinho, R. A. (2003) · Genes & Development · doi:10.1101/gad.1158703 · Cited by 1,033 · see citing works
Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis
Sharpless, N. E., Bardeesy, N., Lee, K.-H., Carrasco, D., Castrillon, D. H., Aguirre, A. J., Wu, E. A., Horner, J. W., & DePinho, R. A. (2001) · Nature · doi:10.1038/35092592 · Cited by 848 · see citing works
Dragging ras back in the ring
Stephen, A. G., Esposito, D., Bagni, R. K., & McCormick, F. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.02.017 · Cited by 795 · see citing works
A "humanized" green fluorescent protein cDNA adapted for high-level expression in mammalian cells
Zolotukhin, S., Potter, M., Hauswirth, W. W., Guy, J., & Muzyczka, N. (1996) · Journal of Virology · doi:10.1128/jvi.70.7.4646-4654.1996 · Cited by 609 · see citing works
Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes
Fisher, G. H., Wellen, S. L., Klimstra, D., Lenczowski, J. M., Tichelaar, J. W., Lizak, M. J., Whitsett, J. A., Koretsky, A., & Varmus, H. E. (2001) · Genes & Development · doi:10.1101/gad.947701 · Cited by 582 · see citing works
Regulating the regulator: post-translational modification of RAS
Ahearn, I. M., Haigis, K. M., Bar‐Sagi, D., & Philips, M. R. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3255 · Cited by 557 · see citing works
Synonymous mutations frequently act as driver mutations in human cancers.
Supek, F., Miñana, B., Valcárcel, J., Gabaldón, T., & Lehner, B. (2014) · Cell · doi:10.1016/j.cell.2014.01.051 · Cited by 553 · see citing works
Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis
Sarkisian, C. J., Keister, B. A., Stairs, D. B., Boxer, R. B., Moody, S. E., & Chodosh, L. A. (2007) · Nature Cell Biology · doi:10.1038/ncb1567 · Cited by 490 · see citing works
Minimal Ras-binding domain of Raf1 can be used as an activation-specific probe for Ras
de Rooij, J., & Bos, J. L. (1997) · Oncogene · doi:10.1038/sj.onc.1201005 · Cited by 450 · see citing works
Protamine-Cre recombinase transgenes efficiently recombine target sequences in the male germ line of mice, but not in embryonic stem cells
O’Gorman, S., Dagenais, N., Qian, M., & Marchuk, Y. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.26.14602 · Cited by 436 · see citing works
RALA and RALBP1 regulate mitochondrial fission at mitosis
Kashatus, D. F., Lim, K.-H., Brady, D. C., Pershing, N. L. K., Cox, A. D., & Counter, C. M. (2011) · Nature Cell Biology · doi:10.1038/ncb2310 · Cited by 380 · see citing works
Self-citation
Tumour maintenance is mediated by eNOS
Lim, K., Ancrile, B. B., Kashatus, D. F., & Counter, C. M. (2008) · Nature · doi:10.1038/nature06778 · Cited by 315 · see citing works
Self-citation
Targeted Genomic Disruption of H-ras and N-ras, Individually or in Combination, Reveals the Dispensability of Both Loci for Mouse Growth and Development
Esteban, L. M., Vicario‐Abejón, C., Fernández‐Salguero, P. M., Fernández‐Medarde, A., Swaminathan, N., Yienger, K., Lopez, E., Malumbres, M., McKay, R. D. G., Ward, J. M., et al. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.5.1444-1452.2001 · Cited by 298 · see citing works
Wildtype Kras2 can inhibit lung carcinogenesis in mice
Zhang, Z., Wang, Y., Vikis, H. G., Johnson, L., Liu, G., Li, J., Anderson, M. W., Sills, R. C., Hong, H. L. T., Devereux, T. R., et al. (2001) · Nature Genetics · doi:10.1038/ng721 · Cited by 295 · see citing works
Allosteric modulation of Ras positions Q61 for a direct role in catalysis
Buhrman, G., Holzapfel, G. A., Fetics, S., & Mattos, C. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0912226107 · Cited by 246 · see citing works
Mutation-Specific RAS Oncogenicity Explains NRAS Codon 61 Selection in Melanoma
Burd, C. E., Liu, W., Huynh, M. V., Waqas, M. A., Gillahan, J. E., Clark, K. S., Fu, K., Martin, B. L., Jeck, W. R., Souroullas, G. P., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-14-0729 · Cited by 214 · see citing works
Oncogenic and Wild-type Ras Play Divergent Roles in the Regulation of Mitogen-Activated Protein Kinase Signaling
Young, A., Lou, D., & McCormick, F. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0231 · Cited by 211 · see citing works
Differential Arginylation of Actin Isoforms Is Regulated by Coding Sequence–Dependent Degradation
Zhang, F., Saha, S., Shabalina, S. A., & Kashina, A. S. (2010) · Science · doi:10.1126/science.1191701 · Cited by 206 · see citing works
Sos-mediated cross-activation of wild-type Ras by oncogenic Ras is essential for tumorigenesis
Jeng, H., Taylor, L. J., & Bar‐Sagi, D. (2012) · Nature Communications · doi:10.1038/ncomms2173 · Cited by 176 · see citing works
The genetic basis of susceptibility to lung tumors in mice
Malkinson, A. M. (1989) · Toxicology · doi:10.1016/0300-483x(89)90062-0 · Cited by 152 · see citing works
Rare Codons Regulate KRas Oncogenesis
Lampson, B. L., Pershing, N. L., Prinz, J. A., Lacsina, J. R., Marzluff, W. F., Nicchitta, C. V., MacAlpine, D. M., & Counter, C. M. (2012) · Current Biology · doi:10.1016/j.cub.2012.11.031 · Cited by 150 · see citing works
Self-citation
Wild-Type H- and N-Ras Promote Mutant K-Ras-Driven Tumorigenesis by Modulating the DNA Damage Response
Grabocka, E., Pylayeva‐Gupta, Y., Jones, M. V., Lubkov, V., Yemanaberhan, E., Taylor, L. J., Jeng, H. H., & Bar‐Sagi, D. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.01.005 · Cited by 141 · see citing works
Mutant K-Ras Activation of the Proapoptotic MST2 Pathway Is Antagonized by Wild-Type K-Ras
Matallanas, D., Romano, D., Al‐Mulla, F., O’Neill, E. E., Al-Ali, W., Crespo, P., Doyle, B. J., Nixon, C., Sansom, O. J., Drosten, M., et al. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.10.016 · Cited by 133 · see citing works
Kras regulatory elements and exon 4A determine mutation specificity in lung cancer
To, M. D., Wong, C. E., Karnezis, A. N., Rosario, R. D., Lauro, R. D., & Balmain, A. (2008) · Nature Genetics · doi:10.1038/ng.211 · Cited by 117 · see citing works
Transformation Efficiency of RasQ61 Mutants Linked to Structural Features of the Switch Regions in the Presence of Raf
Buhrman, G., Wink, G., & Mattos, C. (2007) · Structure · doi:10.1016/j.str.2007.10.011 · Cited by 116 · see citing works
A functional switch from lung cancer resistance to susceptibility at the Pas1 locus in Kras2LA2 mice
To, M. D., Pérez‐Losada, J., Mao, J., Hsu, J., Jacks, T., & Balmain, A. (2006) · Nature Genetics · doi:10.1038/ng1836 · Cited by 69 · see citing works
H-, N- and Kras cooperatively regulate lymphatic vessel growth by modulating VEGFR3 expression in lymphatic endothelial cells in mice
Ichise, T., Yoshida, N., & Ichise, H. (2010) · Development · doi:10.1242/dev.043489 · Cited by 62 · see citing works
A Genetically Defined Normal Human Somatic Cell System to Study Ras Oncogenesis In Vivo and In Vitro
O’Hayer, K., & Counter, C. M. (2006) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(05)07050-3 · Cited by 53 · see citing works
Self-citation
Experimentally Increased Codon Bias in the DrosophilaAdhGene Leads to an Increase in Larval, But Not Adult, Alcohol Dehydrogenase Activity
Hense, W., Anderson, N., Hütter, S., Stephan, W., Parsch, J., & Carlini, D. B. (2009) · Genetics · doi:10.1534/genetics.109.111294 · Cited by 35 · see citing works
Ki-ras gene mutations and absence ofp53 gene mutations in spontaneous and urethane-induced early lung lesions in CBA/J mice
Cazorla, M., Hernández, L., Fernández, P. L., Fabra, À., Peinado, M. A., Dasenbrock, C., Tillmann, T., Kamino, K., Campo, E., Köhler, M., et al. (1998) · Molecular Carcinogenesis · doi:10.1002/(sici)1098-2744(199804)21:4 · Cited by 34 · see citing works
Expression of Human nPTB Is Limited by Extreme Suboptimal Codon Content
Robinson, F., Jackson, R. J., & Smith, C. W. J. (2008) · PLoS ONE · doi:10.1371/journal.pone.0001801 · Cited by 30 · see citing works
The Differential Effects of Wild-Type and Mutated K-Ras on MST2 Signaling Are Determined by K-Ras Activation Kinetics
Romano, D., Maccario, H., Doherty, C., Quinn, N. P., Kölch, W., & Matallanas, D. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.01414-12 · Cited by 30 · see citing works
Inhibition of protein kinase C and proto-oncogene expression by crocetin in NIH/3T3 cells
Wang, C., Cheng, T., Liu, J.-Y., Chou, F., Kuo, M., & Lin, J.-K. (1996) · Molecular Carcinogenesis · doi:10.1002/(sici)1098-2744(199612)17:4 · Cited by 28 · see citing works
Age-Related Macular Degeneration-Associated Silent Polymorphisms in HtrA1 Impair Its Ability To Antagonize Insulin-Like Growth Factor 1
Jacobo, S. M. P., DeAngelis, M. M., Kim, I. K., & Kazlauskas, A. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.01283-12 · Cited by 28 · see citing works
Epistatic interactions govern chemically‐induced lung tumor susceptibility and Kras mutation site in murine C57BL/6J‐ChrA/J chromosome substitution strains
Dwyer‐Nield, L. D., McQuillan, J. J., Hill‐Baskin, A. E., Radcliffe, R. A., You, M., Nadeau, J. H., & Malkinson, A. M. (2009) · International Journal of Cancer · doi:10.1002/ijc.24743 · Cited by 27 · see citing works
Generalized substitution of isoencoding codons shortens the duration of papillomavirus L1 protein expression in transiently gene-transfected keratinocytes due to cell differentiation
Gu, W., Ding, J., Wang, X., Kluyver, R. L. D., Saunders, N. A., Frazer, I. H., & Zhao, K. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm496 · Cited by 26 · see citing works
Mouse Pulmonary Adenoma Susceptibility 1 Locus Is an Expression QTL Modulating Kras-4A
Dassano, A., Colombo, F., Trincucci, G., Frullanti, E., Galvan, A., Pettinicchio, A., Cecco, L. D., Borrego, A., Ibañez, O. M., Dragani, T. A., et al. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004307 · Cited by 17 · see citing works
ARF inhibits the growth and malignant progression of non-small-cell lung carcinoma
Busch, S., Moser, R. D., Gurley, K. E., Kelly‐Spratt, K. S., Liggitt, H. D., & Kemp, C. J. (2013) · Oncogene · doi:10.1038/onc.2013.208 · Cited by 14 · see citing works
Cis-acting genomic elements of the Pas1 locus control Kras mutability in lung tumors
Manenti, G., Trincucci, G., Pettinicchio, A., Amendola, E., Scarfò, M., & Dragani, T. A. (2008) · Oncogene · doi:10.1038/onc.2008.194 · Cited by 14 · see citing works

Flagged first, then by citations

Research works printed but not linked: 3

Horio Y, et al. Ki-ras and p53 mutations are early and late events, respectively, in urethane-in- duced pulmonary carcinogenesis in A/J mice. Mol Carcinog. 1996;17(4):217-223.
Collado M, et al. Tumour biology: Senes- cence in premalignant tumours. Nat Cell Biol. 2005;436(7051):642-642.
Kimchi-Sarfaty C, et al. A "silent" polymorphism in the MDR1 gene changes substrate specificity. Science. 2007;315(5811):525-528.

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A stress‐induced tyrosine‐tRNA depletion response mediates codon‐based translational repression and growth suppression
Huh, D., Passarelli, M. C., Gao, J., Dusmatova, S. N., Goin, C., Fish, L., Pinzaru, A. M., Molina, H., Ren, Z., McMillan, E. A., et al. (2020) · The EMBO Journal · doi:10.15252/embj.2020106696 · Cited by 43 · see citing works
RHOA takes the RHOad less traveled to cancer
Schaefer, A., & Der, C. J. (2022) · Trends in cancer · doi:10.1016/j.trecan.2022.04.005 · Cited by 41 · see citing works
Absolute Quantification of Endogenous Ras Isoform Abundance
Mageean, C. J., Griffiths, J. R., Smith, D. L., Clague, M. J., & Prior, I. A. (2015) · PLoS ONE · doi:10.1371/journal.pone.0142674 · Cited by 36 · see citing works
Effects of codon usage on gene expression are promoter context dependent
Yang, Q., Lyu, X., Zhao, F., & Liu, Y. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa1253 · Cited by 35 · see citing works
tRNA biology in the omics era: Stress signalling dynamics and cancer progression
Orioli, A. (2016) · BioEssays · doi:10.1002/bies.201600158 · Cited by 31 · see citing works
Translation Regulation in Skin Cancer from a tRNA Point of View
Grafanaki, K., Anastasakis, D. G., Kyriakopoulos, G. C., Skeparnias, I., Georgiou, S., & Stathopoulos, C. (2018) · Epigenomics · doi:10.2217/epi-2018-0176 · Cited by 30 · see citing works
Mutation bias within oncogene families is related to proliferation-specific codon usage
Benisty, H., Weber, M. L., Hernandez‐Alias, X., Schaefer, M. H., & Serrano, L. G. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2016119117 · Cited by 29 · see citing works
Codon optimality in cancer
Gillen, S. L., Waldron, J. A., & Bushell, M. (2021) · Oncogene · doi:10.1038/s41388-021-02022-x · Cited by 29 · see citing works
The renewed battle against RAS-mutant cancers
Zhang, F., & Cheong, J. K. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2155-8 · Cited by 29 · see citing works
KRAS Oncoprotein Expression Is Regulated by a Self-Governing eIF5A-PEAK1 Feed-Forward Regulatory Loop
Fujimura, K., Wang, H., Watson, F., & Klemke, R. L. (2018) · Cancer Research · doi:10.1158/0008-5472.can-17-2873 · Cited by 29 · see citing works
Capturing the primordial Kras mutation initiating urethane carcinogenesis
Li, S., MacAlpine, D. M., & Counter, C. M. (2020) · Nature Communications · doi:10.1038/s41467-020-15660-8 · Cited by 28 · see citing works
Self-citation
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Nyíri, K., Koppány, G., & Vértessy, B. G. (2020) · Cancer and Metastasis Reviews · doi:10.1007/s10555-020-09914-6 · Cited by 27 · see citing works
H-Ras and K-Ras Oncoproteins Induce Different Tumor Spectra When Driven by the Same Regulatory Sequences
Drosten, M., Simón-Carrasco, L., Hernández-Porras, I., Lechuga, C. G., Blasco, M. T., Jacob, H. K. C., Fabbiano, S., Potenza, N., Bustelo, X. R., Guerra, C. E., et al. (2016) · Cancer Research · doi:10.1158/0008-5472.can-16-2925 · Cited by 26 · see citing works
Calmodulin disrupts plasma membrane localization of farnesylated KRAS4b by sequestering its lipid moiety
Grant, B., Enomoto, M., Back, S.-I., Lee, K., Gebregiworgis, T., Ishiyama, N., Ikura, M., & Marshall, C. B. (2020) · Science Signaling · doi:10.1126/scisignal.aaz0344 · Cited by 26 · see citing works
Short stretches of rare codons regulate translation of the transcription factor ZEB2 in cancer cells
Makhtar, W. R. W., Browne, G. J., Karountzos, A. S., Stevens, C., Alghamdi, Y. S., Bottrill, A. R., Mistry, S. C., Smith, E. M., Bushel, M., Pringle, J. H., et al. (2017) · Oncogene · doi:10.1038/onc.2017.273 · Cited by 25 · see citing works
Dysregulation of tRNA methylation in cancer: Mechanisms and targeting therapeutic strategies
Yuan, W., Zhang, R., Lyu, H., Xiao, S., Guo, D., Zhang, Q., Ali, D. W., Michalak, M., Chen, X., Zhou, C., et al. (2024) · Cell Death Discovery · doi:10.1038/s41420-024-02097-x · Cited by 23 · see citing works
Wild-type Kras expands and exhausts hematopoietic stem cells
Sasine, J. P., Himburg, H. A., Termini, C. M., Roos, M. M., Tran, E., Zhao, L., Kan, J., Li, M., Zhang, Y., de Barros, S. C., et al. (2018) · JCI Insight · doi:10.1172/jci.insight.98197 · Cited by 16 · see citing works
Self-citation
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Montalvo, S. K., Li, L., & Westover, K. D. (2016) · Future Oncology · doi:10.2217/fon-2016-0363 · Cited by 15 · see citing works
Genetically manipulating endogenous Kras levels and oncogenic mutations in vivo influences tissue patterning of murine tumorigenesis
Roux, Ö. L., Pershing, N. L., Kaltenbrun, E., Newman, N. J., Everitt, J. I., Baldelli, E., Pierobon, M., Petricoin, E. F., & Counter, C. M. (2022) · eLife · doi:10.7554/elife.75715 · Cited by 15 · see citing works
Self-citation
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Waters, A. M., Bagni, R., Portugal, F. H., & Hartley, J. L. (2016) · PLoS ONE · doi:10.1371/journal.pone.0163272 · Cited by 14 · see citing works
Signaling levels mold the RAS mutation tropism of urethane
Li, S., & Counter, C. M. (2021) · eLife · doi:10.7554/elife.67172 · Cited by 13 · see citing works
Self-citation
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Valenzuela, C. A., Saucedo, S., & Llano, M. (2024) · Viruses · doi:10.3390/v16040502 · Cited by 12 · see citing works
Expression of transgenes enriched in rare codons is enhanced by the MAPK pathway
Peterson, J. J., Li, S., Kaltenbrun, E., Roux, Ö. L., & Counter, C. M. (2020) · Scientific Reports · doi:10.1038/s41598-020-78453-5 · Cited by 11 · see citing works
Self-citation
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Sawyer, J. K., Kabiri, Z., Montague, R. A., Allen, S. R., Stewart, R. K., Paramore, S. V., Cohen, E., Zaribafzadeh, H., Counter, C. M., & Fox, D. T. (2020) · PLoS Genetics · doi:10.1371/journal.pgen.1009228 · Cited by 10 · see citing works
Self-citation
Orb2 enables rare-codon-enriched mRNA expression during Drosophila neuron differentiation
Stewart, R. K., Nguyen, P., Laederach, A., Volkan, P., Sawyer, J. K., & Fox, D. T. (2024) · Nature Communications · doi:10.1038/s41467-024-48344-8 · Cited by 8 · see citing works
Isoform-Specific Effects of Wild-Type Ras Genes on Carcinogen-Induced Lung Tumorigenesis in Mice
Weyandt, J. D., Carney, J. M., Pavlisko, E. N., Xu, M., & Counter, C. M. (2016) · PLoS ONE · doi:10.1371/journal.pone.0167205 · Cited by 7 · see citing works
Self-citation
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Liu, Y., Sharp, J. S., H-T., D., Kahn, R., Schwalbe, H., Buhr, F., & Prestegard, J. H. (2017) · PLoS ONE · doi:10.1371/journal.pone.0180566 · Cited by 7 · see citing works
Role of silent mutations in KRAS-mutant tumors
Lu, J. G., Zhou, C., Pan, F., Liu, H., Jiang, H., Zhong, H., & Han, B. (2024) · Chinese Medical Journal · doi:10.1097/cm9.0000000000003405 · Cited by 6 · see citing works
RAS: Circuitry and therapeutic targeting
Singh, G., Thakur, N., & Kumar, U. (2022) · Cellular Signalling · doi:10.1016/j.cellsig.2022.110505 · Cited by 5 · see citing works
Non-canonical genomic driver mutations of urethane carcinogenesis
Li, S., & Counter, C. M. (2022) · PLoS ONE · doi:10.1371/journal.pone.0267147 · Cited by 4 · see citing works
Self-citation
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Nandan, P. K., & Jayanthi, S. (2025) · Discover Oncology · doi:10.1007/s12672-025-02783-x · Cited by 3 · see citing works
RNA modifications in cancer and their detection: a review
Yu, B.-Y., & Ueda, H. (2026) · Japanese Journal of Clinical Oncology · doi:10.1093/jjco/hyag018 · Cited by 3 · see citing works
KRAS oncogenic mutations in benign tumors: adenomatoid odontogenic tumor as a model
Coura, B. P., Guimarães, L. M., Gomez, R. S., & Gomes, C. C. (2025) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2025.108552 · Cited by 3 · see citing works
An Insight into Codon Pattern Analysis of Autophagy Genes Associated with Virus Infection
Singhal, S., Kumar, U., Alqahtani, T., Rzhepakovsky, I. V., Khandia, R., Pandey, M. K., Alqahtani, S., Alharbi, H. M., & Kamal, M. A. (2023) · Current Pharmaceutical Design · doi:10.2174/1381612829666230418093308 · Cited by 3 · see citing works
Absolute Quantitation of GTPase Protein Abundance
Hood, F. E., Sahraoui, Y. M. E., Jenkins, R. E., & Prior, I. A. (2021) · Methods in molecular biology · doi:10.1007/978-1-0716-1190-6_4 · Cited by 3 · see citing works
Analysis of RAS as a tumor suppressorPreprint
Kenney, C., & Stites, E. C. (2017) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/153692 · Cited by 3 · see citing works
A stress-induced Tyrosine tRNA depletion response mediates codon-based translational repression and growth suppressionPreprint
Huh, D., Passarelli, M. C., Gao, J., Dusmatova, S. N., Goin, C., Fish, L., Pinzaru, A. M., Molina, H., McMillan, E. A., Asgharian, H., et al. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/416727 · Cited by 3 · see citing works
Cancer modeling in colorectal organoids reveals intrinsic differences between oncogenic RAS and BRAF variantsPreprint
Post, J. B., Hami, N., Lohuis, J. O., van de Ven, M., de Korte‐Grimmerink, R., Stangl, C., Stelloo, E., Verlaan-Klink, I., van Rheenen, J., & Snippert, H. J. G. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/860122 · Cited by 3 · see citing works
Maf1 cooperates with progesterone receptor to repress RNA polymerase III transcription of select tRNAs
Finlay-Schultz, J., Vinod-Paul, K., Erickson, B., Fettig, L. M., Hastings, B. S., Johnson, D. L., Bentley, D. L., Kabos, P., & Sartorius, C. A. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf1176 · Cited by 2 · see citing works
Computational Random Mutagenesis to Investigate RAS Mutant Signaling
Stites, E. C. (2023) · Methods in molecular biology · doi:10.1007/978-1-0716-3008-2_15 · Cited by 1 · see citing works
Characterisation of the cellular response to defective translational termination
Ploumakis, A. (2018) · University of Birmingham Institutional Research Archive (University of Birmingham)
Role of RAS signaling in Hedgehog-associated embryonal rhabdomyosarcoma
Bauer, J. (2019) · doi:10.53846/goediss-7239
Faculty Opinions recommendation of Interrogating the protein interactomes of RAS isoforms identifies PIP5K1A as a KRAS-specific vulnerability.
O’Bryan, J. P. (2019) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.733983450.793559493
Different Oncogenes and Reproductive Histories Shape the Progression of Distinct Premalignant Clones in Multistage Mouse Breast Cancer Models
Linscott, M. P., Ren, J. R., Gestl, S. A., & Gunther, E. J. (2024) · American Journal Of Pathology · doi:10.1016/j.ajpath.2024.02.018
Hététogénéité intratumorale et dynamique des populations du carcinome hépatocellulaire : impact de l’intensité de la signalisation Ras/MAPK Erk
Lozano, A. (2021) · theses.fr (ABES) · doi:10.70675/a2b1195ez9acdz4848za284z48d03d642274
Mécanismes moléculaires et cellulaires de formation et de dissolution des « processing bodies » en conditions physiologiques et physiopathologiques
Vidal-Cruchez, O. (2021) · theses.fr (ABES) · doi:10.70675/0c0e4622zadcfz40b9zb89ez6f22a14b8866
KRAS mutations in gastrointestinal cancers: New insights from pathogenic mechanisms to therapeutic challenges
Yang, X., Tao, X., Qi, W., Luo, R., Lan, T., Xie, K., Cai, Y., Gao, F., Lv, Y., Liu, C., et al. (2026) · Journal of Pharmaceutical Analysis · doi:10.1016/j.jpha.2026.101718
Oncogenes have the most distinct codon biases in the genome and codon signatures that oppose tumor suppressor genesPreprint
Mathur, C., Davis, E. T., Ehrbar, D. J., Omeoga, H. C., Endres, L., Byrne, S. R., Begley, U., Dedon, P. C., & Begley, T. J. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.08.21.746283

Authors: Pershing, N. L. K., Lampson, B. L., Belsky, J. A., Kaltenbrun, E., MacAlpine, D. M., & Counter, C. M.
Affiliations: Duke Medical Center (US)
ORCID: Pershing, Nicole L.K.
Lampson, Benjamin L.
Belsky, Jason A.
MacAlpine, David M.
Counter, Christopher M.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2014-12-01
Volume: 125
Issue: 1
Pages: 222-233
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci77627
PMC: PMC4382256
OpenAlex: W2114694498
Cited by: 77
References: 53
Citations by year: 2026: 2 · 2025: 3 · 2024: 5 · 2023: 7 · 2022: 7 · 2021: 8 · 2020: 9 · 2019: 4 · 2018: 11 · 2017: 8 · 2016: 10 · 2015: 3
FWCI: 2.87
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Brigham and Women's Hospital
National Cancer Institute (R03CA165927, R01CA154630, P30CA014236)
National Institute of General Medical Sciences (T32GM071340)
Duke Cancer Institute
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords: KRAS, rare codons, codon usage bias, synonymous mutations, oncogenic mutations, tumor suppression, carcinogen-induced tumors, protein expression, growth arrest, mouse model
MeSH terms: Adenoma, Animals, Cells, Cultured, Codon, Female, Humans, Lung Neoplasms, Male, Mice, Inbred C57BL, Mice, Transgenic, Urethane, Proto-Oncogene Proteins p21(ras), Tumor Burden, Cell Proliferation, Mice, 129 Strain, Carcinogenesis

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Rare codons capacitate Kras-driven de novo tumorigenesis

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