The DOI matches its Crossref record; 12 of the 12 references it cites were found in a registry or an index.
p53 and NF-κB Coregulate Proinflammatory Gene Responses in Human Macrophages
Open accessAbstract
Macrophages are sentinel immune cells that survey the tissue microenvironment, releasing cytokines in response to both exogenous insults and endogenous events such as tumorigenesis. Macrophages mediate tumor surveillance and therapy-induced tumor regression; however, tumor-associated macrophages (TAM) and their products may also promote tumor progression. Whereas NF-κB is prominent in macrophage-initiated inflammatory responses, little is known about the role of p53 in macrophage responses to environmental challenge, including chemotherapy or in TAMs. Here, we report that NF-κB and p53, which generally have opposing effects in cancer cells, coregulate induction of proinflammatory genes in primary human monocytes and macrophages. Using Nutlin-3 as a tool, we demonstrate that p53 and NF-κB rapidly and highly induce interleukin (IL)-6 by binding to its promoter. Transcriptome analysis revealed global p53/NF-κB co-regulation of immune response genes, including several chemokines, which effectively induced human neutrophil migration. In addition, we show that p53, activated by tumor cell paracrine factors, induces high basal levels of macrophage IL-6 in a TAM model system [tumor-conditioned macrophages (TCM)]. Compared with normal macrophages, TCMs exhibited higher p53 levels, enhanced p53 binding to the IL-6 promoter, and reduced IL-6 levels upon p53 inhibition. Taken together, we describe a mechanism by which human macrophages integrate signals through p53 and NF-κB to drive proinflammatory cytokine induction. Our results implicate a novel role for macrophage p53 in conditioning the tumor microenvironment and suggest a potential mechanism by which p53-activating chemotherapeutics, acting upon p53-sufficient macrophages and precursor monocytes, may indirectly impact tumors lacking functional p53. Cancer Res; 74(8); 2182–92. ©2014 AACR.
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Cites
In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2
Vassilev, L. T., Vu, B. T., Graves, B., Carvajal, D., Podlaski, F., Filipovic, Z., Kong, N., Kammlott, U., Lukacs, C., Klein, C., et al. (2004) · Science · doi:10.1126/science.1092472 · Cited by 4,661
Mdm2 promotes the rapid degradation of p53
Haupt, Y., Maya, R., Kazaz, A., & Oren, M. (1997) · Nature · doi:10.1038/387296a0 · Cited by 4,506
Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas
Xue, W., Zender, L., Miething, C., Dickins, R. A., Hernando, E., Krizhanovsky, V., Cordon-Cardo, C., & Lowe, S. W. (2007) · Nature · doi:10.1038/nature05529 · Cited by 2,473
IKKβ Links Inflammation and Tumorigenesis in a Mouse Model of Colitis-Associated Cancer
Greten, F. R., Eckmann, L., Greten, T. F., Park, J. M., Li, Z.-W., Egan, L. J., Kagnoff, M. F., & Karin, M. (2004) · Cell · doi:10.1016/j.cell.2004.07.013 · Cited by 2,433
Crosstalk in NF-κB Signaling Pathways
Oeckinghaus, A., Hayden, M. S., & Ghosh, S. (2011) · Nature Immunology · doi:10.1038/ni.2065 · Cited by 1,942
A Chemical Inhibitor of p53 That Protects Mice from the Side Effects of Cancer Therapy
Komarov, P. G., Komarova, E. A., Kondratov, R. V., Christov-Tselkov, K., Coon, J. S., Chernov, M. V., & Gudkov, A. V. (1999) · Science · doi:10.1126/science.285.5434.1733 · Cited by 1,270
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Menendez, D., Nguyen, T.-A., Freudenberg, J. M., Mathew, V. J., Anderson, C. W., Jothi, R., & Resnick, M. A. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt504 · Cited by 154
Self-citationThe Toll-like receptor gene family is integrated into human DNA damage and p53 networks
Menendez, D., Shatz, M., Azzam, K., Garantziotis, S., Fessler, M. B., & Resnick, M. A. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1001360 · Cited by 148
Self-citationKadekaro, A. L., Chen, J., Yang, J., Chen, S., Jameson, J., Swope, V. B., Cheng, T., Kadakia, M., & Abdel-Malek, Z. (2012) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-11-0436 · Cited by 122
Cited by
Metabolic Reprogramming of Immune Cells in Cancer Progression
Biswas, S. K. (2015) · Immunity · doi:10.1016/j.immuni.2015.09.001 · Cited by 721
Dunphy, G., Flannery, S. M., Almine, J. F., Connolly, D. J., Paulus, C., Jønsson, K. L., Jakobsen, M. R., Nevels, M. M., Bowie, A. G., & Unterholzner, L. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.07.034 · Cited by 648
“Because cooperation between p53 and p65 in the transactivation of innate immune genes, including IL-6 and CCL20, has been observed (Lowe et al., 2014), it remains to be investigated whether p53 acts as a transcription factor and/or has a role in NF-kB activation during the transcriptional response to etoposide.”
BackgroundHall, B. M., Balan, V., Gleiberman, A. S., Strom, E., Krasnov, P., Virtuoso, L. P., Rydkina, E., Vujcic, S., Balan, K., Gitlin, I. I., et al. (2017) · Aging · doi:10.18632/aging.101268 · Cited by 407
p53, cancer and the immune response
Blagih, J., Buck, M. D., & Vousden, K. H. (2020) · Journal of Cell Science · doi:10.1242/jcs.237453 · Cited by 333
Ham, I.-H., Oh, H. J., Jin, H., Bae, C. A., Jeon, S.-M., Choi, K. S., Son, S.-Y., Han, S.-U., Brekken, R. A., Lee, D., et al. (2019) · Molecular Cancer · doi:10.1186/s12943-019-0972-8 · Cited by 264
Metadata
- Authors
- Lowe, J. M., Menendez, D., Bushel, P. R., Shatz, M., Kirk, E. L., Troester, M. A., Garantziotis, S., Fessler, M. B., & Resnick, M. A.
- Venue
- Cancer Research
- Published
- 2014-04-15
- Volume
- 74
- Issue
- 8
- Pages
- 2182-2192
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2084268370
- Cited by
- 171
- References
- 12
- FWCI
- 3.89
- Type
- journal article
- Language
- en
- Open access
- green
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- Lowe, J. M., Menendez, D., Bushel, P. R., Shatz, M., Kirk, E. L., Troester, M. A., Garantziotis, S., Fessler, M. B., & Resnick, M. A. (2014). p53 and NF-κB Coregulate Proinflammatory Gene Responses in Human Macrophages. Cancer Research. https://doi.org/10.1158/0008-5472.can-13-1070
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