P73 is regulated by tyrosine kinase c-Abl in the apoptotic response to DNAdamage

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 da mage(1,2). The tyrosine kinase c-Abl is activated by certain DNA-damaging a gents(3) and contributes to the induction of programmed cell death (apoptos is) by p53-dependent and p53-independent mechanisms(4). Here we show that c -Abl binds to p73 in cells, interacting through its SH3 domain with the car boxy-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 b een exposed to ionizing radiation. Our results show that c-Abl stimulates p 73-mediated transactivation and apoptosis. This regulation of p73 by c-Abl in response to PNA damage is also demonstrated by a failure of ionizing-rad iation-induced apoptosis after disruption of the c-Abl-p73 interaction. The se findings show that p73 is regulated by a c-Abl-dependent mechanism and t hat p73 participates in the apoptotic response to DNA damage.