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 to the 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.
Yuan
Z M
ZM
Department of Cancer Cell Biology, Harvard School of Public Health, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Shioya
H
H
Ishiko
T
T
Sun
X
X
Gu
J
J
Huang
Y Y
YY
Lu
H
H
Kharbanda
S
S
Weichselbaum
R
R
Kufe
D
D
D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D019556:COS Cells; D002460:Cell Line; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016147:Genes, Tumor Suppressor; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D018909:src Homology Domains
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011994:Recombinant Proteins; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D016315:Proto-Oncogene Proteins c-abl