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  • The EMBO Journal (2003) 22, 1289 - 1301
  • doi:10.1093/emboj/cdg129

p53 induction and activation of DDR1 kinase counteract p53-mediated apoptosis and influence p53 regulation through a positive feedback loop

Pat P. Ongusaha1, Jong-il Kim2, Li Fang3, Tai W. Wong4, George D. Yancopoulos5, Stuart A. Aaronson3 and Sam W. Lee1

  1. Cancer Biology Program, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine and Harvard Medical School, Boston, MA 02115, USA
  2. Present address: Department of Biochemistry, College of Medicine, Hallym University, Chunchon, 200-702, Korea
  3. Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, NY 10029, USA
  4. Oncology Drug Discovery Group, Bristol-Meyer Squibb Pharmaceutical Research Institutes, Princeton, NJ 08543, USA
  5. Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591, USA

Correspondence to:

Sam W. Lee, E-mail: slee2@caregroup.harvard.edu

Received 4 November 2002; Accepted 23 January 2003; Revised 22 January 2003

DDR1, discoidin domain receptor 1, belongs to a subfamily of tyrosine kinase receptors with an extracellular domain homologous to Dictyostellium discoideum protein discoidin 1. We showed that DDR1 is a direct p53 transcriptional target, and that DNA damage induced a p53-dependent DDR1 response associated with activation of its tyrosine kinase. We further demonstrated that DDR1 activated the MAPK cascade in a Ras-dependent manner. Whereas levels of p53, phosphoserine-15 p53, p21, ARF and Bcl-XL were increased in response to exogenous overexpression of activated DDR1, dominant-negative DDR1 inhibited irradiation-induced MAPK activation and p53, phosphoserine-15 p53, as well as induced p21 and DDR1 levels, suggesting that DDR1 functions in a feedforward loop to increase p53 levels and at least some of its effectors. Nonetheless, inhibition of DDR1 function resulted in strikingly increased apoptosis of wild-type p53-containing cells in response to genotoxic stress through a caspase-dependent pathway. These results strongly imply that this p53 response gene must predominately act to alleviate the adverse effects of stress induced by p53 on its target cell.

  • Keywords:

    • apoptosis,
    • cell survival,
    • DDR1,
    • p53,
    • Ras,
    • Raf,
    • MAPK