Tumor suppressor p53 stole the AKT in hypoxia
Zhong Yun, Peter M. Glazer
Zhong Yun, Peter M. Glazer
Published May 11, 2015
Citation Information: J Clin Invest. 2015;125(6):2264-2266. https://doi.org/10.1172/JCI82058.
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Commentary

Tumor suppressor p53 stole the AKT in hypoxia

Abstract

The presence of hypoxia within a tumor is associated with poor clinical outcome, which is often exacerbated by loss of the tumor suppressor p53. In the presence of functional p53, hypoxic conditions promote apoptosis; however, the p53-dependent genes that mediate this process are not well understood. In this issue of the JCI, Leszczynska and colleagues identify a p53-dependent six-gene signature that is specifically induced in hypoxia and mediates apoptosis. In patients with a variety of cancers, downregulation of this gene signature was associated with poor clinical outcome. Induction of p53-dependent apoptosis under hypoxia was mediated by AKT inhibition, and treatment with the combination of an AKT inhibitor and ionizing radiation decreased tumor size in a p53-deficient xenograft model more substantially than either single-agent treatment. The results of this study provide important insight into p53-mediated apoptosis under hypoxia and suggest that AKT inhibition has therapeutic potential for inducing apoptosis in hypoxic, p53-deficient cancers.

Authors

Zhong Yun, Peter M. Glazer

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Figure 1

p53-dependent apoptosis via inhibition of AKT activation under severe hypoxia.

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p53-dependent apoptosis via inhibition of AKT activation under severe hy...
Severe hypoxia promotes transcription of the proapoptotic gene Bnip3l, which requires both HIF-1α and p53 binding at the Bnip3l promoter. Previous studies have suggested that hypoxia alters the transcriptional activity of p53 by inducing p53 to function as a transrepressor as opposed to a transactivator. In this issue, Leszczynska and colleagues identified a six-gene signature (blue box) that promotes apoptosis in p53-expressing cells under hypoxia. The products of two of these genes, PHLDA3 and INPP5D, prevent phosphorylation and activation AKT, thereby promoting apoptosis.