Nutlin-3 induces HO-1 expression by activating JNK in a transcription-independent manner of p53

  • Authors:
    • Yun-Jeong Choe
    • Sun-Young Lee
    • Kyung Won Ko
    • Seok Joon Shin
    • Ho-Shik Kim
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  • Published online on: December 23, 2013     https://doi.org/10.3892/ijo.2013.2227
  • Pages: 761-768
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Abstract

A recent study reported that p53 can induce HO-1 by directly binding to the putative p53 responsive element in the HO-1 promoter. In this study, we report that nutlin-3, a small molecule antagonist of HDM2, induces the transcription of HO-1 in a transcription-independent manner of p53. Nutlin-3 induced HO-1 expression at the level of transcription in human cancer cells such as U2OS and RKO cells. This induction of HO-1 did not occur in SAOS cells in which p53 was mutated and was prevented by knocking down the p53 protein using p53 siRNA transfection, but not by PFT-α, an inhibitor of the transcriptional activity of p53. Accompanying HO-1 expression, nutlin-3 stimulated the accumulation of ROS and the phosphorylation of MAPKs such as JNK, p38 MAPK and ERK1/2. Nutlin-3-induced HO-1 expression was suppressed by TEMPO, a ROS scavenger, and chemical inhibitors of JNK and p38 MAPK but not ERK1/2. In addition, nutlin‑3-induced phosphorylation of JNK but not p38 MAPK was inhibited by TEMPO. Notably, the levels of nutlin-3-induced ROS were correlated with the mitochondrial translocation of p53 and this induction was prevented by PFT-μ, an inhibitor of the mitochondrial translocation of p53. Consistent with the effect of the ROS scavenger and MAPK inhibitors, PFT-μ reduced HO-1 expression and the phosphorylation of JNK induced by nutlin-3. In the experiments of analyzing cell death, the knockdown of HO-1 augmented nutlin-3-induced apoptosis. Collectively, these results suggest that nutlin-3 induces HO-1 expression via the activation of both JNK which is dependent on ROS generated by p53 translocated to the mitochondria and p38 MAPK which appears to be stimulated by a ROS-independent mechanism, and this HO-1 induction may inhibit nutlin-3-induced apoptosis, constituting a negative feedback loop of p53-induced apoptosis.
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2014-March
Volume 44 Issue 3

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Spandidos Publications style
Choe Y, Lee S, Ko KW, Shin SJ and Kim H: Nutlin-3 induces HO-1 expression by activating JNK in a transcription-independent manner of p53. Int J Oncol 44: 761-768, 2014
APA
Choe, Y., Lee, S., Ko, K.W., Shin, S.J., & Kim, H. (2014). Nutlin-3 induces HO-1 expression by activating JNK in a transcription-independent manner of p53. International Journal of Oncology, 44, 761-768. https://doi.org/10.3892/ijo.2013.2227
MLA
Choe, Y., Lee, S., Ko, K. W., Shin, S. J., Kim, H."Nutlin-3 induces HO-1 expression by activating JNK in a transcription-independent manner of p53". International Journal of Oncology 44.3 (2014): 761-768.
Chicago
Choe, Y., Lee, S., Ko, K. W., Shin, S. J., Kim, H."Nutlin-3 induces HO-1 expression by activating JNK in a transcription-independent manner of p53". International Journal of Oncology 44, no. 3 (2014): 761-768. https://doi.org/10.3892/ijo.2013.2227