The DOI matches its Crossref record; 10 of the 10 references it cites were found in a registry or an index.
Altered RNA Splicing by Mutant p53 Activates Oncogenic RAS Signaling in Pancreatic Cancer
Open accessAbstract
SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is driven by co-existing mutations in KRAS and TP53. However, how these mutations collaborate to promote this cancer is unknown. Here we uncover sequence-specific changes in RNA splicing enforced by mutant p53 which enhance KRAS activity. Mutant p53 increases expression of splicing regulator hnRNPK to promote inclusion of cytosine-rich exons within GTPase Activating Proteins (GAPs), negative regulators of RAS family members. Mutant p53-enforced GAP isoforms lose cell membrane association, leading to heightened KRAS activity. Preventing cytosine-rich exon inclusion in mutant KRAS/p53 PDACs decreases tumor growth. Moreover, mutant p53 PDACs are sensitized to inhibition of splicing via spliceosome inhibitors. These data provide insight into co-enrichment of KRAS and p53 mutations and therapeutics targeting this mechanism in PDAC.
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Citations
Cites
Near-optimal probabilistic RNA-seq quantification
Bray, N. L., Pimentel, H., Melsted, P., & Pachter, L. (2016) · Nature Biotechnology · doi:10.1038/nbt.3519 · Cited by 9,723
Genomic analyses identify molecular subtypes of pancreatic cancer
Bailey, P., Chang, D. K., Nones, K., Johns, A. L., Patch, A.-M., Gingras, M.-C., Miller, D. K., Christ, A. N., Bruxner, T. J. C., Quinn, M. C., et al. (2016) · Nature · doi:10.1038/nature16965 · Cited by 3,621 · cited 9×
“Approximately 40% of PDACs have hotspot missense TP53mutations, while 30% have truncating mutations (Bailey et al., 2016; Collisson et al., 2011; Moffitt et al., 2015).”
BackgroundMethodInfluentialSelf-citationMoffitt, R. A., Marayati, R., Flate, E. L., Volmar, K. E., Loeza, S. G. H., Hoadley, K. A., Rashid, N. U., Williams, L. A., Eaton, S. C., Chung, A. H., et al. (2015) · Nature Genetics · doi:10.1038/ng.3398 · Cited by 2,194
Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome
Olive, K. P., Tuveson, D. A., Ruhe, Z. C., Yin, B., Willis, N. A., Bronson, R. T., Crowley, D., & Jacks, T. (2004) · Cell · doi:10.1016/j.cell.2004.11.004 · Cited by 1,308
Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor
Janes, M. R., Zhang, J., Li, L.-S., Hansen, R., Peters, U., Guo, X., Chen, Y., Babbar, A., Firdaus, S. J., Darjania, L., et al. (2018) · Cell · doi:10.1016/j.cell.2018.01.006 · Cited by 1,172 · cited 1×
“These differences have led to development of G12C inhibitors (Janes et al., 2018); however, there is no targeted therapy for other mutant forms of KRAS.”
BackgroundA Global Map of p53 Transcription-Factor Binding Sites in the Human Genome
Wei, C.-L., Wu, Q., Vega, V. B., Chiu, K. P., Ng, P., Zhang, T., Shahab, A., Yong, H. C., Fu, Y., Weng, Z., et al. (2006) · Cell · doi:10.1016/j.cell.2005.10.043 · Cited by 1,141
Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations
Hunter, J. C., Manandhar, A., Carrasco, M. A., Gurbani, D., Gondi, S., & Westover, K. D. (2015) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-15-0203 · Cited by 786 · cited 3×
“Previous reports suggest that oncogenic KRAS with specific activating mutations remain susceptible to GAP-mediated GTP hydrolysis (Hunter et al., 2015).”
BackgroundInfluentialSRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition
Kim, E., Ilagan, J. O., Liang, Y., Daubner, G. M., Lee, S. C.-W., Ramakrishnan, A., Li, Y., Chung, Y. R., Micol, J.-B., Murphy, M. E., et al. (2015) · Cancer Cell · doi:10.1016/j.ccell.2015.04.006 · Cited by 575
Self-citationMutant p53 Drives Pancreatic Cancer Metastasis through Cell-Autonomous PDGF Receptor β Signaling
Weissmueller, S., Manchado, E., Saborowski, M., Morris, J. P., Wagenblast, E., Davis, C. A., Moon, S.-H., Pfister, N. T., Tschaharganeh, D. F., Kitzing, T., et al. (2014) · Cell · doi:10.1016/j.cell.2014.01.066 · Cited by 466 · cited 2×
“Inducible shRNAs against TP53 and Trp53 (human andmurine p53) or renilla (R) were cloned into the TRMPV-Neo vector (pSIN-TREdsRed-miR30-PGK-Venus-IRES-NeoR) as previously described (Weissmueller et al., 2014; Zuber et al., 2011).”
BackgroundMethodSelf-citationSynthetic Lethal Vulnerabilities in KRAS-Mutant Cancers
Aguirre, A. J., & Hahn, W. C. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a031518 · Cited by 90
Self-citation
Cited by
Pancreatic cancer: Advances and challenges
Halbrook, C. J., Lyssiotis, C. A., Pasca di Magliano, M., & Maitra, A. (2023) · Cell · doi:10.1016/j.cell.2023.02.014 · Cited by 1,321
RNA splicing dysregulation and the hallmarks of cancer
Bradley, R. K., & Anczuków, O. (2023) · Nature Reviews Cancer · doi:10.1038/s41568-022-00541-7 · Cited by 579
Self-citationMasugi, Y., Takamatsu, M., Tanaka, M., Hara, K., Inoue, Y., Hamada, T., Suzuki, T., Arita, J., Hirose, Y., Kawaguchi, Y., et al. (2023) · The Journal of Pathology: Clinical Research · doi:10.1002/cjp2.323 · Cited by 23
Qiao, Z., Ge, J., He, W., Xu, X., & He, J. (2022) · Computational and Mathematical Methods in Medicine · doi:10.1155/2022/8979404 · Cited by 14
Retracted
Metadata
- Authors
- Escobar-Hoyos, L. F., Penson, A., Kannan, R., Cho, H., Pan, C.-H., Singh, R. K., Apken, L. H., Hobbs, G. A., Luo, R., Lecomte, N., Babu, S., Pan, F. C., Alonso-Curbelo, D., Morris, J. P., Askan, G., Grbovic-Huezo, O., Ogrodowski, P., Bermeo, J., Saglimbeni, J., Cruz, C. D., Ho, Y.-J., Lawrence, S. A., Melchor, J. P., Goda, G. A., Bai, K., Pastore, A., Hogg, S. J., Raghavan, S., Bailey, P., Chang, D. K., Biankin, A., Shroyer, K. R., Wolpin, B. M., Aguirre, A. J., Ventura, A., Taylor, B., Der, C. J., Dominguez, D., Kümmel, D., Oeckinghaus, A., Lowe, S. W., Bradley, R. K., Abdel-Wahab, O., & Leach, S. D.
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2020-08
- Volume
- 38
- Issue
- 2
- Pages
- 198-211.e8
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W3036630705
- Cited by
- 162
- References
- 10
- FWCI
- 6.57
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Escobar-Hoyos, L. F., Penson, A., Kannan, R., Cho, H., Pan, C.-H., Singh, R. K., Apken, L. H., Hobbs, G. A., Luo, R., Lecomte, N., Babu, S., Pan, F. C., Alonso-Curbelo, D., Morris, J. P., Askan, G., Grbovic-Huezo, O., Ogrodowski, P., Bermeo, J., Saglimbeni, J., . . . Leach, S. D. (2020). Altered RNA Splicing by Mutant p53 Activates Oncogenic RAS Signaling in Pancreatic Cancer. Cancer Cell. https://doi.org/10.1016/j.ccell.2020.05.010
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
