p73 is regulated by tyrosine kinase c-Abl in the apoptotic response to DNA damage

The protein p73 is a structural and functional homologue of the p53 tumour-suppressor protein but, unlike p53, it is not induced in response to DNA damage,. The tyrosine kinase c-Abl is activated by certain DNA-damaging agents and contributes tothe induction of programmed cell death (apoptosis) by p53-dependent and p53-independent mechanisms. Here we show that c-Abl binds to p73 in cells, interacting through its SH3 domain with the carboxy-terminal homo-oligomerization domain of p73. c-Abl phosphorylates p73 on a tyrosine residue at position 99 both in vitro and in cells that have been exposed to ionizing radiation. Our results show that c-Abl stimulates p73-mediated transactivation and apoptosis. This regulation of p73 by c-Abl in response to DNA damage is also demonstrated by a failure of ionizing-radiation-induced apoptosis after disruption of the c-Abl–p73 interaction. These findings show that p73 is regulated by a c-Abl-dependent mechanism and that p73 participates in the apoptotic response to DNA damage.

[1]  R. Weichselbaum,et al.  Activation of the c-Abl tyrosine kinase in the stress response to DMA-damaging agents , 1995, Nature.

[2]  M. Oren,et al.  Regulation of mdm2 expression by p53: alternative promoters produce transcripts with nonidentical translation potential. , 1994, Genes & development.

[3]  R. Bronson,et al.  Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene , 1991, Cell.

[4]  A. Yang,et al.  Monoallelically Expressed Gene Related to p53 at 1p36, a Region Frequently Deleted in Neuroblastoma and Other Human Cancers , 1997, Cell.

[5]  B. Vogelstein,et al.  Participation of p53 protein in the cellular response to DNA damage. , 1991, Cancer research.

[6]  R. Weichselbaum,et al.  Regulation of DNA damage-induced apoptosis by the c-Abl tyrosine kinase. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[7]  D. Housman,et al.  p53-dependent apoptosis modulates the cytotoxicity of anticancer agents , 1993, Cell.

[8]  S. Powell,et al.  High Frequency and Error-prone DNA Recombination in Ataxia Telangiectasia Cell Lines (*) , 1996, The Journal of Biological Chemistry.

[9]  D. Baltimore,et al.  Abl protein-tyrosine kinase selects the Crk adapter as a substrate using SH3-binding sites. , 1994, Genes & development.

[10]  Y. Shiloh,et al.  Interaction between ATM protein and c-Abl in response to DNA damage , 1997, Nature.

[11]  Scott W. Lowe,et al.  p53 is required for radiation-induced apoptosis in mouse thymocytes , 1993, Nature.

[12]  B. Vogelstein,et al.  p53 functions as a cell cycle control protein in osteosarcomas , 1990, Molecular and cellular biology.

[13]  C. Purdie,et al.  Thymocyte apoptosis induced by p53-dependent and independent pathways , 1993, Nature.

[14]  C. Sawyers,et al.  The nuclear tyrosine kinase c-abl negatively regulates cell growth , 1994, Cell.

[15]  S. Inoue,et al.  Functional interaction between DNA-PK and c-Abl in response to DNA damage , 1997, Nature.

[16]  D. Baltimore,et al.  Ataxia telangiectasia mutant protein activates c-Abl tyrosine kinase in response to ionizing radiation , 1997, Nature.

[17]  R. Weichselbaum,et al.  Role for c-Abl tyrosine kinase in growth arrest response to DNA damage , 1996, Nature.

[18]  W. Kaelin,et al.  Viral Oncoproteins Discriminate between p53 and the p53 Homolog p73 , 1998, Molecular and Cellular Biology.

[19]  Xinbin Chen,et al.  The potential tumor suppressor p73 differentially regulates cellular p53 target genes. , 1998, Cancer research.

[20]  L. Zon,et al.  c-Abl Activation Regulates Induction of the SEK1/Stress-activated Protein Kinase Pathway in the Cellular Response to 1-β-D-Arabinofuranosylcytosine (*) , 1995, The Journal of Biological Chemistry.

[21]  W. Kaelin,et al.  p73 is a human p53-related protein that can induce apoptosis , 1997, Nature.