Regulation of p73-mediated apoptosis by c-Jun N-terminal kinase

Emma V Jones , Mark J Dickman , Alan J Whitmarsh (1)

1 Faculty of Life Sciences [Manchester]

The c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) signalling pathway is a major mediator of stress responses in cells, including the response to DNA damage. DNA damage also causes the stabilisation and activation of p73, a member of the p53 family of transcription factors. p73, like p53, can mediate apoptosis by up-regulating the expression of pro-apoptotic genes, including Bax and PUMA. Changes in p73 expression have been linked to tumor progression particularly in neuroblastomas, while in tumors that feature inactivated p53 there is evidence that p73 may mediate the apoptotic response to chemotherapeutic agents. Here we demonstrate a novel link between the JNK signalling pathway and p73. We use pharmacological and genetic approaches to show that JNK is required for p73-mediated apoptosis induced by the DNA damaging agent, cisplatin. JNK forms a complex with p73 and phosphorylates it at several Ser/Thr residues. The mutation of JNK phosphorylation sites in p73 abrogates cisplatin-induced stabilisation of p73 protein, leads to a reduction in p73 transcriptional activity, and reduced p73-mediated apoptosis. Our results demonstrate that the JNK pathway is an important regulator of DNA damage-induced apoptosis mediated by p73.

Mots clés: Life Sciences

Emma V Jones, Mark J Dickman, Alan J Whitmarsh. Regulation of p73-mediated apoptosis by c-Jun N-terminal kinase. Biochemical Journal, 2007, 405 (3), pp.617-623. ⟨10.1042/BJ20061778⟩. ⟨hal-00478707⟩