title: p73 is regulated by tyrosine kinase c-Abl in the apoptotic response to DNA damage.
abstract: 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.
authors.affiliation: Department of Cancer Cell Biology, Harvard School of Public Health, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Z M
authors.initials: ZM
authors.lastname: Yuan
authors.forename: H
authors.initials: H
authors.lastname: Shioya
authors.forename: T
authors.initials: T
authors.lastname: Ishiko
authors.forename: X
authors.initials: X
authors.lastname: Sun
authors.forename: J
authors.initials: J
authors.lastname: Gu
authors.forename: Y Y
authors.initials: YY
authors.lastname: Huang
authors.forename: H
authors.initials: H
authors.lastname: Lu
authors.forename: S
authors.initials: S
authors.lastname: Kharbanda
authors.forename: R
authors.initials: R
authors.lastname: Weichselbaum
authors.forename: D
authors.initials: D
authors.lastname: Kufe
mesh_terms: 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
chemical_list: 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