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  • The EMBO Journal (2009) 28, 2100 - 2113
  • doi:10.1038/emboj.2009.164

Published online: 18 June 2009

Differential regulation of p53 and p21 by MKRN1 E3 ligase controls cell cycle arrest and apoptosis

Eun-Woo Lee1, Min-Sik Lee1, Suzanne Camus2,*, Jaewang Ghim1,*, Mi-Ran Yang1, Wonkyung Oh1, Nam-Chul Ha3, David P Lane2 and Jaewhan Song1

  1. Department of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon, Korea
  2. Department of Cell Cycle Control, Institute of Molecular and Cell Biology, Proteos, Singapore
  3. Department of Manufacturing Pharmacy, College of Pharmacy, Pusan National University, Busan, Korea

Correspondence to:

Jaewhan Song, Department of Biotechnology and Bioengineering, Sungkyunkwan University, 300 Chunchun-dong, Jangan-gu, Suwon, Kyungi-do 440-746, Korea. Tel.: +82 31 290 7807; Fax: +82 31 290 7882; E-mail: jso678@skku.edu

*Present address: Centre de Medicina Regenerativa de Barcelona, Dr Aiguader 88, Barcelona 08003, Spain

*Present address: Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, Kyungbuk 790-784, South Korea

Received 8 January 2009; Accepted 22 May 2009

Makorin Ring Finger Protein 1 (MKRN1) is a transcriptional co-regulator and an E3 ligase. Here, we show that MKRN1 simultaneously functions as a differentially negative regulator of p53 and p21. In normal conditions, MKRN1 could destabilize both p53 and p21 through ubiquitination and proteasome-dependent degradation. As a result, depletion of MKRN1 induced growth arrest through activation of p53 and p21. Interestingly, MKRN1 used earlier unknown sites, K291 and K292, for p53 ubiquitination and subsequent degradation. Under severe stress conditions, however, MKRN1 primarily induced the efficient degradation of p21. This regulatory process contributed to the acceleration of DNA damage-induced apoptosis by eliminating p21. MKRN1 depletion diminished adriamycin or ultraviolet-induced cell death, whereas ectopic expression of MKRN1 facilitated apoptosis. Furthermore, MKRN1 stable cell lines that constantly produced low levels of p53 and p21 exhibited stabilization of p53, but not p21, with increased cell death on DNA damage. Our results indicate that MKRN1 exhibits dual functions of keeping cells alive by suppressing p53 under normal conditions and stimulating cell death by repressing p21 under stress conditions.

  • Keywords:

    • Hdm2 (Mdm2),
    • MKRN1,
    • p21,
    • p53,
    • ubiquitination