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KRAB-type zinc-finger protein Apak specifically regulates p53-dependent apoptosis

Nature Cell Biology volume 11, pages 580–591 (2009)Cite this article

Abstract

Only a few p53 regulators have been shown to participate in the selective control of p53-mediated cell cycle arrest or apoptosis. How p53-mediated apoptosis is negatively regulated remains largely unclear. Here we report that Apak (ATM and p53-associated KZNF protein), a Krüppel-associated box (KRAB)-type zinc-finger protein, binds directly to p53 in unstressed cells, specifically downregulates pro-apoptotic genes, and suppresses p53-mediated apoptosis by recruiting KRAB-box-associated protein (KAP)-1 and histone deacetylase 1 (HDAC1) to attenuate the acetylation of p53. Apak inhibits p53 activity by interacting with ATM, a previously identified p53 activator. In response to stress, Apak is phosphorylated by ATM and dissociates from p53, resulting in activation of p53 and induction of apoptosis. These findings revealed Apak to be a negative regulator of p53-mediated apoptosis and showed the dual role of ATM in p53 regulation.

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Figure 1: Apak negatively regulates p53-mediated apoptosis.
Figure 2: Apak interacts with p53 both in vitro and in vivo.
Figure 3: Apak recruits histone acetylase to regulate p53 acetylation.
Figure 4: Apak requires ATM to repress p53 activity in unstressed cells.
Figure 5: Apak is phosphorylated by ATM in response to cellular stress.
Figure 6: Apak phosphorylation on Ser 68 is critical for p53-mediated apoptosis.
Figure 7: ATM and KAP-1 coordinate the selection of p53 target gene expression with KZNF proteins.
Figure 8: A model for Apak function and regulation in unstressed and DNA-damaged cells.

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Acknowledgements

We are grateful to Bert Vogelstein, Michael B. Kastan, Qimin Zhan, Wei Gu, Jiandong Chen, Yue Xiong, Shengcai Lin, Gang Pei and Weiguo Zhu for providing materials; Yi Tie, Heping Pan, Qiao Sun, Juntao Yang, Xiushan Yin, Dahu Li, Bo Dong, Shaofei Zhong, Bin Li and Yanzhi Yuan for technical assistance; and Wei Gu, Yue Xiong, Shengcai Lin, Zigang Dong, Yi Rao and Chengrong Lu for critical reading of the manuscript. This study was supported by Chinese National Basic Research Programs 2007CB914601 (L.Z.) and 2006CB910802 (F.H., L.Z.), Chinese National Natural Science Foundation Projects 30621063 (F.H.) and 30600310, 30871373 (C.T.), and the Beijing Science and Technology NOVA Program 2007A063 (L.Z.).

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  1. hefc@nic.bmi.ac.cn

Authors and Affiliations

  1. State Key Laboratory of Proteomics, Beijing Proteomics Research Center, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing, 100850, China

    Chunyan Tian, Guichun Xing, Ping Xie, Kefeng Lu, Jing Nie, Jian Wang, Li Li, Mei Gao, Lingqiang Zhang & Fuchu He

  2. Department of Biology Sciences and Biotechnology, Tsinghua University, Beijing, 100084, China

    Ping Xie, Jing Nie & Fuchu He

  3. Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China

    Fuchu He

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Tian, C., Xing, G., Xie, P. et al. KRAB-type zinc-finger protein Apak specifically regulates p53-dependent apoptosis. Nat Cell Biol 11, 580–591 (2009). https://doi.org/10.1038/ncb1864

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