ATF3 and Fra1 have opposite functions in JNK- and ERK-dependent DNA damage responses.

M. Hamdi, H.E. Popeijus, F. Carlotti, J.M. Janssen, C. van der Burgt, P. Cornelissen-Steijger, B. van de Water, R.C. Hoeben, K. Matsuo, H. van Dam

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    Abstract

    JNK and ERK MAP kinases regulate cellular responses to genotoxic stress in a cell type and cell context-dependent manner. However, the factors that determine and execute JNK- and ERK-controlled stress responses are only partly known. In this study, we investigate the roles of the AP-1 components ATF3 and Fra1 in JNK- and ERK-dependent cell cycle arrest and apoptosis. We show that the anti-cancer drug cisplatin or UV light activates both JNK and ERK in human glioblastoma cells lacking functional p53. Inhibition experiments of JNK or ERK activities revealed that the ERK pathway strongly promotes cisplatin- and UV-induced apoptosis in these glioblastoma cells. Furthermore, JNK but not ERK is required for ATF3 induction, and both ERK and JNK are necessary for post-transcriptional induction of Fra1 in response to cisplatin or UV. Knock-down of ATF3 and Fra1 results in increased and decreased cisplatin-induced apoptosis, respectively, indicating that ATF3 is an anti-apoptotic JNK effector and Fra1 is a pro-apoptotic ERK/JNK effector. Knock-down experiments also revealed that ATF3 and Fra1, respectively, enhance and reduce S-phase arrest through differential modulation of the Chk1-Cdk2 pathway. Thus, we identify novel reciprocal functions of ATF3 and Fra1 in JNK- and ERK-dependent DNA damage responses.
    Original languageEnglish
    Pages (from-to)487-496
    JournalDna Repair
    Volume7
    Issue number3
    DOIs
    Publication statusPublished - 1 Jan 2008

    Cite this

    Hamdi, M., Popeijus, H. E., Carlotti, F., Janssen, J. M., van der Burgt, C., Cornelissen-Steijger, P., van de Water, B., Hoeben, R. C., Matsuo, K., & van Dam, H. (2008). ATF3 and Fra1 have opposite functions in JNK- and ERK-dependent DNA damage responses. Dna Repair, 7(3), 487-496. https://doi.org/10.1016/j.dnarep.2007.12.004