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Angiogenin functionally interacts with p53 and regulates p53-mediated apoptosis and cell survival

Oncogene volume 31, pages 4835–4847 (2012)Cite this article

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Abstract

Angiogenin, a 14-kDa multifunctional pro-angiogenic growth factor, is upregulated in several types of cancers. Anti-angiogenin monoclonal antibodies used as antagonists inhibited the establishment, progression and metastasis of human cancer cells in athymic mice (Olson et al., 1994). Silencing angiogenin and inhibition of angiogenin's nuclear translocation blocked cell survival and induced cell death in B-lymphoma and endothelial cells latently infected with Kaposi sarcoma-associated herpesvirus (Sadagopan et al., 2009), suggesting that actively proliferating cancer cells could be inducing angiogenin for inhibiting apoptotic pathways. However, the mechanism of cell survival and apoptosis regulation by angiogenin and their functional significance in cancer is not known. We demonstrate that angiogenin interacts with p53 and colocalizes in the nucleus. Silencing endogenous angiogenin induced p53 promoter activation and p53 target gene (p53, p21 and Bax) expression, downregulated anti-apoptotic Bcl-2 gene expression and increased p53-mediated cell death. In contrast, angiogenin expression blocked pro-apoptotic Bax and p21 expression, induced Bcl-2 and blocked cell death. Angiogenin also co-immunoprecipitated with p53 regulator protein Mdm2. Angiogenin expression resulted in the inhibition of p53 phosphorylation, increased p53–Mdm2 interaction, and consequently increased ubiquitination of p53. Taken together, these studies demonstrate that angiogenin promotes the inhibition of p53 function to mediate anti-apoptosis and cell survival. Our results reveal for the first time a novel p53 interacting function of angiogenin in anti-apoptosis and survival of cancer cells and suggest that targeting angiogenin could be an effective therapy for several cancers.

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Acknowledgements

This study was supported in part by Public Health Service grants, AI 091767 and the RFUMS—HM Bligh Cancer Research Fund to BC. We thank Dr AP Rapoport (University of Maryland) for providing p53 constructs. We thank Dr B Vogelstein (Johns Hopkins University) for the p53+/+ and p53−/− HCT116 cell lines. We thank Keith Philibert for critically reading the manuscript and Bob Dickinson for FACS analysis at the RFUMS core facility.

Author contributions: SS, MVV and BC designed the experiments. SS, MVV, SC, NP, VB and NSW performed the experiments. MVV, SS and BC wrote the paper.

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  1. S Sadagopan and M V Veettil: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Microbiology and Immunology, H.M. Bligh Cancer Research Laboratories, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA

    S Sadagopan, M V Veettil, S Chakraborty, N Sharma-Walia, N Paudel, V Bottero & B Chandran

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  1. S Sadagopan
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  2. M V Veettil
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Correspondence to B Chandran.

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Sadagopan, S., Veettil, M., Chakraborty, S. et al. Angiogenin functionally interacts with p53 and regulates p53-mediated apoptosis and cell survival. Oncogene 31, 4835–4847 (2012). https://doi.org/10.1038/onc.2011.648

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