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:

Poly(ADP-ribosyl)ation of p53 induces gene-specific transcriptional repression of MTA1

Oncogene volume 31, pages 5099–5107 (2012)Cite this article

Subjects

Abstract

The metastasis-associated protein 1 (MTA1) is overexpressed in various human cancers and is closely connected with aggressive phenotypes; however, little is known about the transcriptional regulation of the MTA1 gene. This study identified the MTA1 gene as a target of p53-mediated transrepression. The MTA1 promoter contains two putative p53 response elements (p53REs), which were repressed by the p53-inducing drug 5-fluorouracil (5-FU). Notably, 5-FU treatment decreased MTA1 expression only in p53 wild-type cells. p53 and histone deacetylases 1/2 were recruited, and acetylation of H3K9 was decreased on the promoter region including the p53REs after 5-FU treatment. Proteomics analysis of the p53 repressor complex, which was pulled down by the MTA1 promoter, revealed that the poly(ADP-ribose) polymerase 1 (PARP-1) was part of the complex. Interestingly, p53 was poly(ADP-ribose)ylated by PARP-1, and the p53-mediated transrepression of the MTA1 gene required poly(ADP-ribose)ylation of p53. In summary, we report a novel function for poly(ADP-ribose)ylation of p53 in the gene-specific regulation of the transcriptional mode of p53 on the promoter of MTA1.

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

  • Cartharius K, Frech K, Grote K, Klocke B, Haltmeier M, Klingenhoff A et al. (2005). MatInspector and beyond: promoter analysis based on transcription factor binding sites. Bioinformatics 21: 2933–2942.

    Article  CAS  PubMed  Google Scholar 

  • Denslow SA, Wade PA . (2007). The human Mi-2/NuRD complex and gene regulation. Oncogene 26: 5433–5438.

    Article  CAS  PubMed  Google Scholar 

  • Estève PO, Chin HG, Pradhan S . (2005). Human maintenance DNA (cytosine-5)-methyltransferase and p53 modulate expression of p53-repressed promoters. Proc Natl Acad Sci USA 102: 1000–1005.

    Article  PubMed  PubMed Central  Google Scholar 

  • Godar S, Ince TA, Bell GW, Feldser D, Donaher JL, Bergh J et al. (2008). Growth-inhibitory and tumor- suppressive functions of p53 depend on its repression of CD44 expression. Cell 134: 62–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Juan LJ, Shia WJ, Chen MH, Yang WM, Seto E, Lin YS et al. (2000). Histone deacetylases specifically down-regulate p53-dependent gene activation. J Biol Chem 275: 20436–20443.

    Article  CAS  PubMed  Google Scholar 

  • Kai L, Wang J, Ivanovic M, Chung YT, Laskin WB, Schulze-Hoepfner F et al. (2011). Targeting prostate cancer angiogenesis through metastasis-associated protein 1 (MTA1). Prostate 71: 268–280.

    Article  CAS  PubMed  Google Scholar 

  • Kanai M, Hanashiro K, Kim SH, Hanai S, Boulares AH, Miwa M et al. (2007). Inhibition of Crm1-p53 interaction and nuclear export of p53 by poly(ADP-ribosyl)ation. Nat Cell Biol 9: 1175–1183.

    Article  CAS  PubMed  Google Scholar 

  • Kim MY, Zhang T, Kraus WL . (2005). Poly(ADP-ribosyl)ation by PARP-1: ‘PAR-laying’ NAD+ into a nuclear signal. Genes Dev 19: 1951–1967.

    Article  CAS  PubMed  Google Scholar 

  • Kraus WL. (2008). Transcriptional control by PARP-1: chromatin modulation, enhancer-binding, coregulation, and insulation. Curr Opin Cell Biol 20: 294–302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krishnakumar R, Kraus WL. (2010). The PARP side of the nucleus: molecular actions, physiological outcomes, and clinical targets. Mol Cell 39: 8–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kumari SR, Mendoza-Alvarez H, Alvarez-Gonzalez R. (1998). Functional interactions of p53 with poly(ADP-ribose) polymerase (PARP) during apoptosis following DNA damage: covalent poly(ADP-ribosyl)ation of p53 by exogenous PARP and noncovalent binding of p53 to the M(r) 85 000 proteolytic fragment. Cancer Res 58: 5075–5078.

    CAS  PubMed  Google Scholar 

  • Lewis BC, Klimstra DS, Socci ND, Xu S, Koutcher A, Varmus HE . (2005). The absence of p53 promotes metastasis in a novel somatic mouse model for hepatocellular carcinoma. Mol Cell Biol 25: 1228–1237.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li DQ, Divijendra Natha Reddy S, Pakala SB, Wu, X, Zhang Y et al. (2009a). MTA1 coregulator regulates p53 stability and function. J Biol Chem 284: 34545–34552.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li DQ, Ohshiro K, Reddy SD, Pakala SB, Lee MH, Zhang Y et al. (2009b). E3 ubiquitin ligase COP1 regulates the stability and functions of MTA1. Proc Natl Acad Sci USA 106: 17493–17498.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li DQ, Pakala SB, Reddy SD, Ohshiro K, Peng SH, Lian Y et al. (2010a). Revelation of p53-independent function of MTA1 in DNA damage response via modulation of the p21 WAF1-proliferating cell nuclear antigen pathway. J Biol Chem 285: 10044–10052.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li DQ, Ohshiro K, Khan MN, Kumar R . (2010b). Requirement of MTA1 in ATR-mediated DNA damage checkpoint function. J Biol Chem 285: 19802–19812.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Longley DB, Harkin DP, Johnston PG. (2003). 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 3: 330–338.

    Article  CAS  PubMed  Google Scholar 

  • Lönn P, van der Heide LP, Dahl M, Hellman U, Heldin CH, Moustakas A . (2010). PARP-1 attenuates Smad-mediated transcription. Mol Cell 40: 521–532.

    Article  PubMed  Google Scholar 

  • Lu H, Wang X, Li T, Urvalek AM, Yu L, Li J et al. (2011). Identification of Poly (ADP-ribose) Polymerase-1 (PARP-1) as a Novel Kruppel-like Factor 8-interacting and -regulating Protein. J Biol Chem 286: 20335–20344.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mazumdar A, Wang RA, Mishra SK, Adam L, Bagheri-Yarmand R, Mandal M et al. (2001). Transcriptional repression of oestrogen receptor by metastasis-associated protein 1 corepressor. Nat Cell Biol 3: 30–37.

    Article  CAS  PubMed  Google Scholar 

  • Meek DW, Anderson CW . (2009). Posttranslational modification of p53: cooperative integrators of function. Cold Spring Harb Perspect Biol 1: a000950.

    Article  PubMed  PubMed Central  Google Scholar 

  • Mehrotra P, Riley JP, Patel R, Li F, Voss L, Goenka S . (2011). PARP-14 functions as a transcriptional switch for Stat6-dependent gene activation. J Biol Chem 286: 1767–1776.

    Article  CAS  PubMed  Google Scholar 

  • Mendoza-Alvarez H, Alvarez-Gonzalez R . (2001). Regulation of p53 sequence-specific DNA-binding by covalent poly(ADP-ribosyl)ation. J Biol Chem 276: 36425–36430.

    Article  CAS  PubMed  Google Scholar 

  • Moon HE, Cheon H, Chun KH, Lee SK, Kim YS, Jung BK et al. (2006). Metastasis-associated protein 1 enhances angiogenesis by stabilization of HIF-1alpha. Oncol Rep 16: 929–935.

    CAS  PubMed  Google Scholar 

  • Morton JP, Klimstra DS, Mongeau ME, Lewis BC. (2008). Trp53 deletion stimulates the formation of metastatic pancreatic tumors. Am J Pathol 172: 1081–1087.

    Article  PubMed  PubMed Central  Google Scholar 

  • Na TY, Shin YK, Roh KJ, Kang SA, Hong I, Oh SJ et al. (2009). Liver X receptor mediates hepatitis B virus X protein-induced lipogenesis in hepatitis B virus-associated hepatocellular carcinoma. Hepatology 49: 1122–1131.

    Article  CAS  PubMed  Google Scholar 

  • O'Shaughnessy J, Schwartzberg LS, Danso MA, Rugo HS, Miller K, Yardley DA et al. (2011). A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin (G/C) in metastatic triple-negative breast cancer (TNBC). J Clin Oncol 29 (suppl) (abstract 1007).

    Article  Google Scholar 

  • Petty RD, Samuel LM, Murray GI, MacDonald G, O'Kelly T, Loudon M et al. (2009). APRIL is a novel clinical chemo-resistance biomarker in colorectal adenocarcinoma identified by gene expression profiling. BMC Cancer 9: 434.

    Article  PubMed  PubMed Central  Google Scholar 

  • Porta C, Hadj-Slimane R, Nejmeddine M, Pampin M, Tovey MG, Espert L et al. (2005). Interferons alpha and gamma induce p53-dependent and p53-independent apoptosis, respectively. Oncogene 24: 605–615.

    Article  CAS  PubMed  Google Scholar 

  • Qian H, Lu N, Xue L, Liang X, Zhang X, Fu M et al. (2005). Reduced MTA1 expression by RNAi inhibits in vitro invasion and migration of esophageal squamous cell carcinoma cell line. Clin Exp Metastasis 22: 653–662.

    Article  CAS  PubMed  Google Scholar 

  • Riley T, Sontag E, Chen P, Levine A. (2008). Transcriptional control of human p53-regulated genes. Nat Rev Mol Cell Biol 9: 402–412.

    Article  CAS  PubMed  Google Scholar 

  • Simbulan-Rosenthal CM, Rosenthal DS, Luo R, Smulson ME. (1999). Poly(ADP-ribosyl)ation of p53 during apoptosis in human osteosarcoma cells. Cancer Res 59: 2190–2194.

    CAS  PubMed  Google Scholar 

  • Sung YH, Kim HJ, Devkota S, Roh J, Lee J, Rhee K et al. (2010). Pierce1, a novel p53 target gene contributing to the ultraviolet-induced DNA damage response. Cancer Res 70: 10454–10463.

    Article  CAS  PubMed  Google Scholar 

  • Toh Y, Nicolson GL. (2009). The role of the MTA family and their encoded proteins in human cancers: molecular functions and clinical implications. Clin Exp Metastasis 26: 215–227.

    Article  CAS  PubMed  Google Scholar 

  • Vousden KH, Lane DP. . (2007). p53 in health and disease. Nat Rev Mol Cell Biol 8: 275–283.

    Article  CAS  PubMed  Google Scholar 

  • Wang B, Xiao Z, Ren EC. (2009a). Redefining the p53 response element. Proc Natl Acad Sci USA 106: 14373–14378.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang B, Xiao Z, Ko HL, Ren EC. (2010). The p53 response element and transcriptional repression. Cell Cycle 9: 870–879.

    Article  CAS  PubMed  Google Scholar 

  • Wang SP, Wang WL, Chang YL, Wu CT, Chao YC, Kao SH et al. (2009b). p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug. Nat Cell Biol 11: 694–704.

    Article  CAS  PubMed  Google Scholar 

  • Wesierska-Gadek J, Schmid G, Cerni C. (1996). ADP-ribosylation of wild-type p53 in vitro: binding of p53 protein to specific p53 consensus sequence prevents its modification. Biochem Biophys Res Commun 224: 96–102.

    Article  CAS  PubMed  Google Scholar 

  • Yap TA, Sandhu SK, Carden CP, de Bono JS. (2011). Poly(ADP-ribose) polymerase (PARP) inhibitors: Exploiting a synthetic lethal strategy in the clinic. CA Cancer J Clin 61: 31–49.

    Article  PubMed  Google Scholar 

  • Yoo YG, Kong G, Lee MO. (2006). Metastasis-associated protein 1 enhances stability of hypoxia-inducible factor-1alpha protein by recruiting histone deacetylase 1. EMBO J 25: 1231–1241.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yoo YG, Na TY, Seo HW, Seong JK, Park CK, Shin YK et al. (2008). Hepatitis B virus X protein induces the expression of MTA1 and HDAC1, which enhances hypoxia signaling in hepatocellular carcinoma cells. Oncogene 27: 3405–3413.

    Article  CAS  PubMed  Google Scholar 

  • Zampieri M, Passananti C, Calabrese R, Perilli M, Corbi N, De Cave F et al. (2009). Parp1 localizes within the Dnmt1 promoter and protects its unmethylated state by its enzymatic activity. PLoS One 4: e4717.

    Article  PubMed  PubMed Central  Google Scholar 

  • Zardo G, Caiafa P. (1998). The unmethylated state of CpG islands in mouse fibroblasts depends on the poly(ADP-ribosyl)ation process. J Biol Chem 273: 16517–165120.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the NRF (2009-0080757), and the SRC/ERC (R11-2007-107-01001-0).

Author information

Author notes

  1. M-H Lee and H Na: These authors contributed equally to this work.

Authors and Affiliations

  1. College of Pharmacy and Bio-MAX Institute, Seoul National University, Seoul, Republic of Korea

    M-H Lee, H Na & M-O Lee

  2. College of Pharmacy Seoul National University, Seoul, Republic of Korea

    E-J Kim & M-O Lee

  3. Department of Biochemistry, College of Life Science and Biotechnology and Laboratory Animal Research Center, Yonsei University, Seoul, Republic of Korea

    H-W Lee

Authors
  1. M-H Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H Na
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E-J Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H-W Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M-O Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M-O Lee.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, MH., Na, H., Kim, EJ. et al. Poly(ADP-ribosyl)ation of p53 induces gene-specific transcriptional repression of MTA1. Oncogene 31, 5099–5107 (2012). https://doi.org/10.1038/onc.2012.2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2012.2

Keywords

This article is cited by

Search

Advanced search

Quick links