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

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.

[1]  J. Massagué,et al.  Myc suppression of the p21Cip1 Cdk inhibitor influences the outcome of the p53 response to DNA damage , 2002, Nature.

[2]  T. Taniguchi,et al.  Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. , 2000, Science.

[3]  D. Morrison,et al.  Regulation of Raf-1 and Raf-1 mutants by Ras-dependent and Ras-independent mechanisms in vitro , 1995, Molecular and cellular biology.

[4]  Sam W. Lee,et al.  p53 induction of heparin‐binding EGF‐like growth factor counteracts p53 growth suppression through activation of MAPK and PI3K/Akt signaling cascades , 2001, The EMBO journal.

[5]  M. Hatten,et al.  Discoidin domain receptor 1 functions in axon extension of cerebellar granule neurons. , 2000, Genes & development.

[6]  B. Gusterson,et al.  Expression patterns of the novel receptor-like tyrosine kinase, DDR, in human breast tumours. , 1995, Oncogene.

[7]  J. Schlessinger.  Direct Binding and Activation of Receptor Tyrosine Kinases by Collagen , 1997, Cell.

[8]  C. Der,et al.  Loss of Transgelin in Breast and Colon Tumors and in RIE-1 Cells by Ras Deregulation of Gene Expression through Raf-independent Pathways* , 2002, The Journal of Biological Chemistry.

[9]  T. Pawson,et al.  Discoidin Domain Receptor 1 Tyrosine Kinase Has an Essential Role in Mammary Gland Development , 2001, Molecular and Cellular Biology.

[10]  K. Kinzler,et al.  A simplified system for generating recombinant adenoviruses. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Yunping Lin,et al.  Pidd, a new death-domain–containing protein, is induced by p53 and promotes apoptosis , 2000, Nature Genetics.

[12]  J. Trent,et al.  WAF1, a potential mediator of p53 tumor suppression , 1993, Cell.

[13]  S. Barondes,et al.  Discoidin I is implicated in cell-substratum attachment and ordered cell migration of dictyostelium discoideum and resembles fibronectin , 1984, Cell.

[14]  Y Sawamura,et al.  Receptor protein tyrosine kinase DDR is up‐regulated by p53 protein , 1996, FEBS letters.

[15]  A. Schulze,et al.  Analysis of the transcriptional program induced by Raf in epithelial cells , 2001, Nature Genetics.

[16]  G. Johnson,et al.  Ras-dependent growth factor regulation of MEK kinase in PC12 cells. , 1994, Science.

[17]  J. D. Weber,et al.  The ARF/p53 pathway. , 2000, Current opinion in genetics & development.

[18]  R. Cancedda,et al.  Molecular cloning of trkE, a novel trk-related putative tyrosine kinase receptor isolated from normal human keratinocytes and widely expressed by normal human tissues. , 1993, The Journal of biological chemistry.

[19]  J. L. Pérez,et al.  Identification of two isoforms of the Cak receptor kinase that are coexpressed in breast tumor cell lines. , 1996, Oncogene.

[20]  J. Schlessinger.  Cell Signaling by Receptor Tyrosine Kinases , 2000, Cell.

[21]  Moshe Oren,et al.  The p53 and Mdm2 families in cancer. , 2002, Current opinion in genetics & development.

[22]  K. Agata,et al.  The A5 antigen, a candidate for the neuronal recognition molecule, has homologies to complement components and coagulation factors , 1991, Neuron.

[23]  C. Prives,et al.  p53: puzzle and paradigm. , 1996, Genes & development.

[24]  W. Rutter,et al.  A receptor tyrosine kinase found in breast carcinoma cells has an extracellular discoidin I-like domain. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[25]  M. Goldfarb,et al.  NEP: a novel receptor-like tyrosine kinase expressed in proliferating neuroepithelia. , 1993, Oncogene.

[26]  K. Vousden,et al.  Minireviewp 53 : Death Star able to induce the defensive p 53 response to oncogene , 2000 .

[27]  S. Lowe,et al.  Oncogenic ras Provokes Premature Cell Senescence Associated with Accumulation of p53 and p16INK4a , 1997, Cell.

[28]  F. McCormick,et al.  Opposing Effects of Ras on p53 Transcriptional Activation of mdm2 and Induction of p19ARF , 2000, Cell.

[29]  D. Woods,et al.  Regulation of the p53 pathway by Ras, the plot thickens. , 2001, Biochimica et biophysica acta.

[30]  T. Hunter,et al.  Signaling—2000 and Beyond , 2000, Cell.

[31]  W. Vogel.  Discoidin domain receptors: structural relations and functional implications , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[32]  S. Lowe,et al.  Oncogenic ras activates the ARF-p53 pathway to suppress epithelial cell transformation , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[33]  G. Wahl,et al.  Differential requirement for p19ARF in the p53-dependent arrest induced by DNA damage, microtubule disruption, and ribonucleotide depletion. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[34]  T. Pawson,et al.  The discoidin domain receptor tyrosine kinases are activated by collagen. , 1997, Molecular cell.

[35]  M. Klagsbrun,et al.  Heparin-binding EGF-like growth factor. , 1997, Biochimica et biophysica acta.

[36]  T. Ouchi,et al.  Sustained activation of Ras/Raf/mitogen-activated protein kinase cascade by the tumor suppressor p53. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[37]  T. Ganesan,et al.  The genomic structure of discoidin receptor tyrosine kinase. , 1996, Genome research.

[38]  A. Shelling,et al.  Isolation and characterization of an epithelial-specific receptor tyrosine kinase from an ovarian cancer cell line. , 1994, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[39]  A. Levine,et al.  Surfing the p53 network , 2000, Nature.

[40]  G. Yancopoulos,et al.  An orphan receptor tyrosine kinase family whose members serve as nonintegrin collagen receptors. , 1997, Molecular cell.

[41]  J. Massagué,et al.  Myc suppression of the p21(Cip1) Cdk inhibitor influences the outcome of the p53 response to DNA damage. , 2002, Nature.

[42]  S. Aaronson,et al.  Wild-type p53 triggers a rapid senescence program in human tumor cells lacking functional p53. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[43]  S. Lowe,et al.  Oncogenic ras and p53 Cooperate To Induce Cellular Senescence , 2002, Molecular and Cellular Biology.

[44]  T. Pawson,et al.  Discoidin Domain Receptor 1 Is Activated Independently of β1 Integrin* , 2000, The Journal of Biological Chemistry.

[45]  H. Höfler,et al.  Distinct structural characteristics of discoidin I subfamily receptor tyrosine kinases and complementary expression in human cancer. , 1995, Oncogene.

[46]  A. Levine.  p53, the Cellular Gatekeeper for Growth and Division , 1997, Cell.

[47]  M. Simon,et al.  Receptor Tyrosine Kinases Specific Outcomes from General Signals , 2000, Cell.

[48]  G. Wahl,et al.  Differential requirement for p19ARF in the p53-dependent arrest induced by DNA damage, microtubule disruption, and ribonucleotide depletion , 2000 .

[49]  S. Lowe,et al.  Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. , 1998, Genes & development.