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. 2019 Nov 27;2:436. doi: 10.1038/s42003-019-0669-y

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© This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2019

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 5 — P53LOH is associated with the activation of the mTOR pathway. a ErbB2 inhibition by lapatinib and trastuzumab inhibits mTOR (pS6) in human mutp53 (BT474) cells. b The mTOR (pS6) pathway is more activated in mutp53;ErbB2 (BT474 and SKBR3) than in wtp53 cells (ZR75–30). c Upregulation of wtp53 by nutlin suppresses mTOR signaling in wtp53;ErbB2 cells ZR 75–30, but not in mutp53;ErbB2 SKBR3 cells. d, e Irradiation induces RNA expression of p53 targets Sestrin 2 (d) and p21 (e) in all genotypes p53+/+;ErbB2, p53−/+;ErbB2 and p53H/+;ErbB2 cells. QRT-PCR 24 h post-irradiation. n = 3 independent experiments. *p < 0.05; **p < 0.01; ***p < 0.001. f The mTOR (pS6) pathway is downregulated in the presence of wtp53 allele 24 h after irradiation that is concomitant with p21 upregulation. g irradiation-induced p53LOH in p53H/+;ErbB2 cells is associated with upregulation of mTOR and lack of detectable p21 in the long term. This is in contrast to p53+/+;ErbB2 and p53−/+;ErbB2 cells. Western blot 7 days post-irradiation. HSC70 as a loading control. h Irradiation-induced p53LOH is concomitant with the upregulation of mTOR signaling that is more profound in mutp53 heterozygous tumors. The scale bar represents 50 μm. Hsp90 inhibition by ganetespib (i) and HSF1 inhibition by KRIBB11 (j) suppresses mTOR in mutp53 human BT474 cells. Western blot after 24 h treatment with indicated concentrations. GAPDH as a loading control. k p53LOH after irradiation is associated with both mTOR and HSF1 activation (as indicated by elevated Hsp70) only in p53H/+;ErbB2 cells. Western blot 7 days after irradiation. HSC70 as a loading control. Error bars represent ± SD. Experiments were repeated three times with similar results.