Sensitisation of c-MYC-induced B-lymphoma cells to apoptosis by ATF2.

Abstract

Transcription factors ATF2 (activating transcription factor 2) and ATF7 (activating transcription factor 7) are highly homologous members of the activator protein 1 (AP-1) family. Their activities are growth factor and stress stimulated and they strictly require phosphorylation by mitogen-activated protein (MAP) kinases for their transcriptional functions. In samples of human B-cell lymphomas as well as Eμ-Myc-driven mouse B-cell lymphomas, we find that ATF2 as well as MAP kinase c-Jun N-terminal kinase (JNK) are significantly up-regulated compared with normal human B-cell lines and mouse B cells, respectively. The B cell-specific deletion of ATF2 and ATF7 in mice results in significantly accelerated onset of Eμ-Myc-induced lymphoma. In addition, loss of ATF2/7 desensitises Eμ-Myc lymphoma cells to spontaneous as well as stress-induced apoptosis. Our results therefore suggest that c-MYC induces stress-mediated activation of ATF2 and ATF7 and that these transcription factors regulate apoptosis in response to oncogenic transformation of B cells.Oncogene advance online publication, 18 February 2013; doi:10.1038/onc.2013.28.