Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

p85α mediates p53 K370 acetylation by p300 and regulates its promoter-specific transactivity in the cellular UVB response

Oncogene volume 30, pages 1360–1371 (2011)Cite this article

Subjects

Abstract

Inducible acetylation of p53 at lysine residues has a great impact on regulating the transactivation of this protein, which is associated with cell growth arrest and/or apoptosis under various stress conditions. However, the factor(s) for regulating p53 acetylation remains largely unknown. In the current study, we have shown that p85α, the regulatory subunit of phosphatidylinositol-3-kinase, has a critical role in mediating p53 acetylation and promoter-specific transactivation in the ultraviolet B (UVB) response. Depletion of p85α in mouse embryonic fibroblasts significantly impairs UVB-induced apoptosis, as well as p53 transactivation and acetylation at Lys370 (Lys373 of human p53); however, the accumulation, nuclear translocation and phosphorylation of p53 are not affected. Interestingly, p85α binds to p300, promotes the p300–p53 interaction and the subsequent recruitment of the p53/p300 complex to the promoter region of the specific p53 target gene in response to UVB irradiation. Moreover, ablation of p53 acetylation at Lys370 by site-directed mutagenesis dramatically suppresses UVB-induced expression of the specific p53-responsive gene as well as cell apoptosis. Therefore, we conclude that p85α is a novel regulator of p53-mediated response under certain stress conditions, and targeting the p85α-dependent p53 pathway may be promising for cancer therapy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • An W, Kim J, Roeder RG . (2004). Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53. Cell 117: 735–748.

    Article  CAS  PubMed  Google Scholar 

  • Avantaggiati ML, Ogryzko V, Gardner K, Giordano A, Levine AS, Kelly K . (1997). Recruitment of p300/CBP in p53-dependent signal pathways. Cell 89: 1175–1184.

    Article  CAS  PubMed  Google Scholar 

  • Brooks CL, Gu W . (2003). Ubiquitination, phosphorylation and acetylation: the molecular basis for p53 regulation. Curr Opin Cell Biol 15: 164–171.

    Article  CAS  PubMed  Google Scholar 

  • Brooks CL, Gu W . (2008). p53 activation: a case against Sir. Cancer Cell 13: 377–378.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cao C, Lu S, Kivlin R, Wallin B, Card E, Bagdasarian A et al. (2008). SIRT1 confers protection against UVB- and H(2)O(2)-induced cell death via modulation of p53 and JNK in cultured skin keratinocytes. J Cell Mol Med 4: 4.

    Google Scholar 

  • Chao C, Wu Z, Mazur SJ, Borges H, Rossi M, Lin T et al. (2006). Acetylation of mouse p53 at lysine 317 negatively regulates p53 apoptotic activities after DNA damage. Mol Cell Biol 26: 6859–6869.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eischen CM, Lozano G . (2009). p53 and MDM2: antagonists or partners in crime? Cancer Cell 15: 161–162.

    Article  CAS  PubMed  Google Scholar 

  • Feng L, Lin T, Uranishi H, Gu W, Xu Y . (2005). Functional analysis of the roles of posttranslational modifications at the p53 C terminus in regulating p53 stability and activity. Mol Cell Biol 25: 5389–5395.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Geering B, Cutillas PR, Vanhaesebroeck B . (2007). Regulation of class IA PI3Ks: is there a role for monomeric PI3K subunits? Biochem Soc Trans 35: 199–203.

    Article  CAS  PubMed  Google Scholar 

  • Goodman RH, Smolik S . (2000). CBP/p300 in cell growth, transformation, and development. Genes Dev 14: 1553–1577.

    CAS  PubMed  Google Scholar 

  • Grossman SR . (2001). p300/CBP/p53 interaction and regulation of the p53 response. Eur J Biochem 268: 2773–2778.

    Article  CAS  PubMed  Google Scholar 

  • Gu W, Roeder RG . (1997). Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90: 595–606.

    Article  CAS  PubMed  Google Scholar 

  • Haupt Y, Maya R, Kazaz A, Oren M . (1997). Mdm2 promotes the rapid degradation of p53. Nature 387: 296–299.

    Article  CAS  PubMed  Google Scholar 

  • Iyer NG, Ozdag H, Caldas C . (2004). p300/CBP and cancer. Oncogene 23: 4225–4231.

    Article  CAS  PubMed  Google Scholar 

  • Juan L-J, Shia W-J, Chen M-H, Yang W-M, Seto E, Lin Y-S et al. (2000). Histone deacetylases specifically down-regulate p53-dependent gene activation. J Biol Chem 275: 20436–20443.

    Article  CAS  PubMed  Google Scholar 

  • Kim EJ, Kho JH, Kang MR, Um SJ . (2007). Active regulator of SIRT1 cooperates with SIRT1 and facilitates suppression of p53 activity. Mol Cell 28: 277–290.

    Article  CAS  PubMed  Google Scholar 

  • Kitagawa M, Lee SH, McCormick F . (2008). Skp2 suppresses p53-dependent apoptosis by inhibiting p300. Mol Cell 29: 217–231.

    Article  CAS  PubMed  Google Scholar 

  • Kruse JP, Gu W . (2009). Modes of p53 regulation. Cell 137: 609–622.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kubbutat MHG, Jones SN, Vousden KH . (1997). Regulation of p53 stability by Mdm2. Nature 387: 299–303.

    Article  CAS  PubMed  Google Scholar 

  • Kurash JK, Lei H, Shen Q, Marston WL, Granda BW, Fan H et al. (2008). Methylation of p53 by Set7/9 mediates p53 acetylation and activity in vivo. Mol Cell 29: 392–400.

    Article  CAS  PubMed  Google Scholar 

  • Lain S, Hollick JJ, Campbell J, Staples OD, Higgins M, Aoubala M et al. (2008). Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell 13: 454–463.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Latonen L, Laiho M . (2005). Cellular UV damage responses—functions of tumor suppressor p53. Biochim Biophys Acta 1755: 71–89.

    CAS  PubMed  Google Scholar 

  • Levine AJ, Hu W, Feng Z . (2006). The P53 pathway: what questions remain to be explored? Cell Death Differ 13: 1027–1036.

    Article  CAS  PubMed  Google Scholar 

  • Li M, Luo J, Brooks CL, Gu W . (2002). Acetylation of p53 inhibits its ubiquitination by Mdm2. J Biol Chem 277: 50607–50611.

    Article  CAS  PubMed  Google Scholar 

  • Lill NL, Grossman SR, Ginsberg D, DeCaprio J, Livingston DM . (1997). Binding and modulation of p53 by p300/CBP coactivators. Nature 387: 823–827.

    Article  CAS  PubMed  Google Scholar 

  • Liu G, Chen X . (2006). Regulation of the p53 transcriptional activity. J Cell Biochem 97: 448–458.

    Article  CAS  PubMed  Google Scholar 

  • Liu L, Scolnick DM, Trievel RC, Zhang HB, Marmorstein R, Halazonetis TD et al. (1999). p53 sites acetylated in vitro by PCAF and p300 are acetylated in vivo in response to DNA damage. Mol Cell Biol 19: 1202–1209.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luo J, Field SJ, Lee JY, Engelman JA, Cantley LC . (2005). The p85 regulatory subunit of phosphoinositide 3-kinase down-regulates IRS-1 signaling via the formation of a sequestration complex. J Cell Biol 170: 455–464.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luo J, Li M, Tang Y, Laszkowska M, Roeder RG, Gu W . (2004). Acetylation of p53 augments its site-specific DNA binding both in vitro and in vivo. Prog Natl Acad Sci USA 101: 2259–2264.

    Article  CAS  Google Scholar 

  • Luo J, Nikolaev AY, Imai S, Chen D, Su F, Shiloh A et al. (2001). Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell 107: 137–148.

    Article  CAS  PubMed  Google Scholar 

  • Luo J, Su F, Chen D, Shiloh A, Gu W . (2000). Deacetylation of p53 modulates its effect on cell growth and apoptosis. Nature 408: 377–381.

    Article  CAS  PubMed  Google Scholar 

  • Manning BD, Cantley LC . (2007). AKT/PKB signaling: navigating downstream. Cell 129: 1261–1274.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miled N, Yan Y, Hon WC, Perisic O, Zvelebil M, Inbar Y et al. (2007). Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science 317: 239–242.

    Article  CAS  PubMed  Google Scholar 

  • Olsson A, Manzl C, Strasser A, Villunger A . (2007). How important are post-translational modifications in p53 for selectivity in target-gene transcription and tumour suppression? Cell Death Differ 14: 1561–1575.

    Article  CAS  PubMed  Google Scholar 

  • Pan X, Zhao J, Zhang WN, Li HY, Mu R, Zhou T et al. (2009). Induction of SOX4 by DNA damage is critical for p53 stabilization and function. Proc Natl Acad Sci USA 106: 3788–3793.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pedeux R, Sengupta S, Shen JC, Demidov ON, Saito S, Onogi H et al. (2005). ING2 regulates the onset of replicative senescence by induction of p300-dependent p53 acetylation. Mol Cell Biol 25: 6639–6648.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reczek EE, Flores ER, Tsay AS, Attardi LD, Jacks T . (2003). Multiple response elements and differential p53 binding control Perp expression during apoptosis. Mol Cancer Res 1: 1048–1057.

    CAS  PubMed  Google Scholar 

  • Sakaguchi K, Herrera JE, Saito S, Miki T, Bustin M, Vassilev A et al. (1998). DNA damage activates p53 through a phosphorylation-acetylation cascade. Genes Dev 12: 2831–2841.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sasaki T, Gan EC, Wakeham A, Kornbluth S, Mak TW, Okada H . (2007). HLA-B-associated transcript 3 (Bat3)/Scythe is essential for p300-mediated acetylation of p53. Genes Dev 21: 848–861.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Song L, Li J, Hu M, Huang C . (2008). Both IKKalpha and IKKbeta are implicated in the arsenite-induced AP-1 transactivation correlating with cell apoptosis through NF-kappaB activity-independent manner. Exp Cell Res 314: 2187–2198.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Song L, Li J, Ye J, Yu G, Ding J, Zhang D et al. (2007). p85alpha acts as a novel signal transducer for mediation of cellular apoptotic response to UV radiation. Mol Cell Biol 27: 2713–2731.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Song L, Li J, Zhang D, Liu ZG, Ye J, Zhan Q et al. (2006). IKKbeta programs to turn on the GADD45alpha-MKK4-JNK apoptotic cascade specifically via p50 NF-kappaB in arsenite response. J Cell Biol 175: 607–617.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sykes SM, Mellert HS, Holbert MA, Li K, Marmorstein R, Lane WS et al. (2006). Acetylation of the p53 DNA-binding domain regulates apoptosis induction. Mol Cell 24: 841–851.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tang Y, Luo J, Zhang W, Gu W . (2006). Tip60-dependent acetylation of p53 modulates the decision between cell-cycle arrest and apoptosis. Mol Cell 24: 827–839.

    Article  CAS  PubMed  Google Scholar 

  • Tang Y, Zhao W, Chen Y, Zhao Y, Gu W . (2008). Acetylation is indispensable for p53 activation. Cell 133: 612–626.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ueki K, Fruman DA, Brachmann SM, Tseng YH, Cantley LC, Kahn CR . (2002a). Molecular balance between the regulatory and catalytic subunits of phosphoinositide 3-kinase regulates cell signaling and survival. Mol Cell Biol 22: 965–977.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ueki K, Yballe CM, Brachmann SM, Vicent D, Watt JM, Kahn CR et al. (2002b). Increased insulin sensitivity in mice lacking p85beta subunit of phosphoinositide 3-kinase. Proc Natl Acad Sci USA 99: 419–424.

    Article  CAS  PubMed  Google Scholar 

  • Vaziri H, Dessain SK, Ng Eaton E, Imai SI, Frye RA, Pandita TK et al. (2001). hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 107: 149–159.

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Ouyang W, Li J, Wei L, Ma Q, Zhang Z et al. (2005). Loss of tumor suppressor p53 decreases PTEN expression and enhances signaling pathways leading to activation of activator protein 1 and nuclear factor {kappa}B induced by UV radiation. Cancer Res 65: 6601–6611.

    Article  CAS  PubMed  Google Scholar 

  • Yin Y, Terauchi Y, Solomon GG, Aizawa S, Rangarajan PN, Yazaki Y et al. (1998). Involvement of p85 in p53-dependent apoptotic response to oxidative stress. Nature 391: 707–710.

    Article  CAS  PubMed  Google Scholar 

  • Zhao W, Kruse JP, Tang Y, Jung SY, Qin J, Gu W . (2008). Negative regulation of the deacetylase SIRT1 by DBC1. Nature 451: 587–590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu Z, Luo Z, Li Y, Ni C, Li H, Zhu M . (2009). Human inhibitor of growth 1 inhibits hepatoma cell growth and influences p53 stability in a variant-dependent manner. Hepatology 49: 504–512.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We appreciate the technical help from Dr Dan Liu and the helpful discussion provided by Dr Ailing Li. This project is partially supported by NIH/NCI CA112557, CA119028-05S110, NIH/NIEHS ES010344 and ES012451 (to Dr C Huang); and National Natural Science Foundation of China No. 30871277, 30970594, Beijing Natural Science Foundation 5092022 and 5102035 and the National Key Research and Development Programs on Fundamental Sciences (973 Project) 2011CB503803 (to Dr L Song).

Author information

Authors and Affiliations

  1. Department of Environmental Medicine, Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY, USA

    L Song, J Li, X Shi & C Huang

  2. Department of Cellular Immunology, Beijing Institute of Basic Medical Sciences, Beijing, People's Republic of China

    L Song, M Gao, W Dong, M Hu, Y Hao & Y Li

Authors
  1. L Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. W Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. X Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Y Hao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Y Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. C Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to L Song or C Huang.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Song, L., Gao, M., Dong, W. et al. p85α mediates p53 K370 acetylation by p300 and regulates its promoter-specific transactivity in the cellular UVB response. Oncogene 30, 1360–1371 (2011). https://doi.org/10.1038/onc.2010.506

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2010.506

Keywords

This article is cited by

Search

Advanced search

Quick links